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  • Neutrophils, as “Trojan horses”, participate in the delivery of therapeutical PLGA nanoparticles into a tumor based on the chemotactic effect
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-09
    Jifu Hao; Junlan Chen; Meixiang Wang; Jing Zhao; Jianze Wang; Xingrong Wang; Yuhong Li; Hua Tang

    Abstract Inspired by the fact that leukocytes have innate phagocytic functions and oriented migration capabilities in response to chemoattractants, we have unveiled that endogenous neutrophils as “Trojan horses”, participate in the delivery of nanoparticles in an “in vivo self-armed assembly” manner. Neutrophils were the main population to preferentially sequester the intravenous administrated nanoparticles with an average size of 260 nm. The pre-implantation of CXCL1-laden hydrogels could trigger and induce a targeted signal to attract an influx of neutrophils carrying the therapeutic goods to the desired position. In mouse models of melanoma, the combinatorial regimen of using the PLGA nanoparticles with the CXCL1 hydrogels exhibited superior tumor inhibition capability. This work leveraged the natural phagocytosis of neutrophile and the chemotactic effect of chemokines for targeted delivery. We believe this strategy will improve the therapeutic efficiency of nanoparticle-based delivery systems, especially when the chemokines are implanted at sites of surgical tumor removal, during cancer treatment at the clinic.

    更新日期:2020-01-13
  • Functionalized selenium nanoparticles for targeted siRNA delivery silence Derlin1 and promote antitumor efficacy against cervical cancer
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-12
    Yu Xia; Guoyi Tang; Changbing Wang; Jiayu Zhong; Yi Chen; Liang Hua; Yinghua Li; Hongsheng Liu; Bing Zhu

    Abstract Small interfering RNA (siRNA) exhibits great potential as a novel therapeutic option due to its highly sequence-specific ability to silence genes. However, efficient and safe delivery carriers are required for developing novel therapeutic paradigms. Thus, the successful development of efficient delivery platforms for siRNA is a crucial issue for the development of siRNA-based drugs in cancer treatments. In this study, biocompatible selenium nanoparticles (SeNPs) were loaded with RGDfC peptide to fabricate tumor-targeting gene delivery vehicle RGDfC-SeNPs. Subsequently, RGDfC-SeNPs were loaded with Derlin1-siRNA to fabricate RGDfC-Se@siRNA, which are functionalized selenium nanoparticles. RGDfC-Se@siRNA showed greater uptake in HeLa cervical cancer cells in comparison with that in human umbilical vein endothelial cells (HUVECs), verifying the RGDfC-mediated specific uptake of RGDfC-Se@siRNA. RGDfC-Se@siRNA was capable of entering HeLa cells via clathrin-associated endocytosis, and showed faster siRNA release in a cancer cell microenvironment in comparison with a normal physiological environment. qPCR and western blotting assays both indicated that RGDfC-Se@siRNA exhibited an obvious gene silencing efficacy in HeLa cells. RGDfC-Se@siRNA suppressed the invasion, migration and the proliferation of HeLa cells, and triggered HeLa cell apoptosis. Moreover, RGDfC-Se@siRNA induced the disruption of mitochondrial membrane potentials. Meanwhile, RGDfC-Se@siRNA enhanced the generation of reactive oxygen species (ROS) in HeLa cell, suggesting that mitochondrial dysfunction mediated by ROS might play a significant role in RGDfC-Se@siRNA-induced apoptosis. Interestingly, RGDfC-SeNPs@siRNA exhibited significant antitumor activity in a HeLa tumor-bearing mouse model. Additionally, RGDfC-SeNPs@siRNA is nontoxic to main organ of mouse. The above results indicate that RGDfC-Se@siRNA provides a promising potential for cervical cancer therapy.

    更新日期:2020-01-13
  • Preparation of PLGA-chitosan based nanocarriers for enhancing antibacterial effect of ciprofloxacin in root canal infection
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-13
    Mona G. Arafa; Hadeel A. Mousa; Nagia N. Afifi

    Abstract The aim of this study is to prepare and evaluate the antibacterial and antibiofilm activity of ciprofloxacin (CIP) loaded PLGA nanoparticles (F2) and CIP-PLGA nanoparticles coated with chitosan (F3) versus ciprofloxacin solution (Fl) as a control on Enterococcus faecalis. F2 was prepared using double emulsion evaporation technique then coated with chitosan (F3). The prepared F2 and F3 were evaluated for size, surface charge, encapsulation efficiency, morphology and in vitro release. F1, F2, F3, and Chitosan (CS) were assessed in vitro using agar diffusion technique and biofilm inhibition assay. Finally, biofilm inhibition on teeth using Colony Forming Unit (CFU) was implemented with different concentrations of the three formulae. The results revealed that F2 is 202.9 nm with a negative charge −0.0254 mv, while F3 is 339.6 nm with a positive charge +28.5 mv. The encapsulation efficiency of F2, and F3 was 64% and 78% respectively. The amount released was 92.62% and 78.3% for F2 and F3, respectively, after 72 h, while F1 showed 100% released in the first hour. CS, F1, F2, and F3, showed antibacterial effect with inhibition zone of 12 mm, 22 mm, 20 mm, and 32 mm respectively. Biofilm inhibition of F1, F2, and F3 were 60%, 74%, and 91.8%, respectively. F3 colony count was less than F2, and F1 in all concentrations. It can be concluded that F3 had proven to exhibit potential antibacterial and antibiofilm activity in a controlled release pattern consequently, they can be used as an intra-canal medication.

    更新日期:2020-01-13
  • Albumin-based cancer therapeutics for intraperitoneal drug delivery: a review
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-20
    Leen Van de Sande; Sarah Cosyns; Wouter Willaert; Wim Ceelen

    Abstract Albumin is a remarkable carrier protein with multiple cellular receptor and ligand binding sites, which are able to bind and transport numerous endogenous and exogenous compounds. The development of albumin-bound drugs is gaining increased importance in the targeted delivery of cancer therapy. Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal metastasis (PM). PM is characterized by the presence of widespread metastatic tumor nodules on the peritoneum, mostly originating from gastro-intestinal or gynaecological cancers. Albumin as a carrier for chemotherapy holds considerable promise for IP delivery in patients with PM. Data from recent (pre)clinical trials suggest that IP albumin-bound chemotherapy may result in superior efficacy in the treatment of PM compared to standard chemotherapy formulations. Here, we review the evidence on albumin-bound chemotherapy with a focus on IP administration and its efficacy in PM.

    更新日期:2020-01-13
  • In vitro and in vivo evaluation of didymin cyclodextrin inclusion complexes: characterization and chemosensitization activity
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-20
    Qing Yao; Meng-Ting Lin; Qing-Hua Lan; Zhi-Wei Huang; Ya-Wen Zheng; Xue Jiang; Yin-Di Zhu; Longfa Kou; He-Lin Xu; Ying-Zheng Zhao

    Abstract Didymin is a dietary flavonoid that first found in citrus fruits, and possesses antioxidant properties. Our preliminary experiments first discovered that didymin was able to sensitize the resistant cancer cells against chemotherapeutics and combat multidrug resistance. However, its poor aqueous solubility and resultant low bioavailability limit its potentials as an adjuvant phytochemical drug for chemotherapy. Thus, this study prepared the inclusion complex of didymin with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin to improve its bioavailability and then evaluate their chemosensitization effects. The didymin inclusion complexes formulation was prepared and their host-guest structure was characterized by FT-IR, PXRD, DSC, and SEM techniques. In vitro/in vivo results demonstrated that didymin inclusion complex enhanced its water solubility and orally bioavailability. Furthermore, didymin inclusion complex exerted considerable chemosensitivity potency, and improve the anti-tumor effects of chemotherapeutics in vivo. Therefore, didymin inclusion complex could provide a safe, effective, economical, and adjuvant drug for future treatment of chemoresistant cancers.

    更新日期:2020-01-13
  • [12]aneN3-based multifunctional compounds as fluorescent probes and nucleic acids delivering agents
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-20
    Yong-Guang Gao; Shu-Yuan Huangfu; Suryaji Patil; Quan Tang; Wan Sun; Yu Li; Zhong-Lin Lu; Airong Qian

    Abstract A series of multifunctional compounds (MFCs) 1a–1e based on 1,8-naphthalimide and [12]aneN3 building blocks were designed and synthesized. They were used as not only fluorescent probes for recognition of Cu2+ ions but also as non-viral gene vectors for DNA and RNA delivery. Furthermore, their complexes with Cu2+ (1-Cu) could also selectively stain lysosome in HeLa cells. In order to achieve high performance multifunctional materials, structure-performance relationship of MFCs 1a–1e was studied. It was found that MFCs 1a–1e exhibited highly selective fluorescence turn-off for Cu2+, without interference by other metal ions in aqueous solution. The fluorescence emission of 1a–1e was quenched by a factor of 10-fold, 47-fold, 6-fold, 64-fold, and 15-fold respectively in the presence of Cu2+ ions. Due to high sensitivity, good water solubility, and low cytotoxicity, MFCs 1a–1d were successfully applied in the recognition of Cu2+ and selectively staining lysosome in HeLa cells. Most importantly, MFCs 1a and 1b had excellent HeLa cell selectivity in RNA delivery, and their performances were far better than lipofectamine 2000 and 25 kDa PEI.

    更新日期:2020-01-13
  • Resveratrol loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles for tail vein injection II: pharmacokinetics, tissue distribution and bioavailability
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-20
    Mingfang Wu; Chen Zhong; Yiping Deng; Qian Zhang; Xiaoxue Zhang; Xiuhua Zhao

    Abstract There are many kinds of biological activities of resveratrol itself, but its clinical application is limited by its poor solubility in water and low bioavailability. Therefore, we have prepared glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles (GL-HSA-RESNPs). The purpose of this study was to investigate the bioavailability, pharmacokinetics and tissue distribution of resveratrol in rats after single-dose tail vein injection administration of GL-HSA-RESNPs. A sensitive and reliable high performance liquid chromatography (HPLC) method was established to verify the content of resveratrol in rat plasma and organs. The Cmax value after GL-HSA-RESNPs administration was significantly higher than that of resveratrol suspension (933 ± 76.64 ng/mL vs. 618 ± 42.54 ng/mL, p < .01). The Tmax value obtained after GL-HSA-RESNPs administration was significantly shorter than that after resveratrol suspension administration (0.17 ± 0.01 h vs. 0.25 ± 0.01 h, p < .001). The bioavailability of GL-HSA-RESNPs was 4.25 times higher than that of the pure resveratrol. The concentration of resveratrol in the main organs of rats treated with the GL-HSA-RESNPs was higher than that in rats treated with the pure resveratrol. Rats treated with GL-HSA-RESNPs had the highest concentration of resveratrol in their liver. It is indicated that GL-HSA-RESNPs is a promising liver-targeted delivery system that improves the in vivo bioavailability of resveratrol.

    更新日期:2020-01-13
  • SPA: a peptide antagonist that acts as a cell-penetrating peptide for drug delivery
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-24
    Jingjing Song; Sujie Huang; Zhengzheng Zhang; Bo Jia; Huan Xie; Ming Kai; Wei Zhang

    Abstract Although cell-penetrating peptides (CPPs) has been proven to be efficient transporter for drug delivery, ideal peptide vectors for tumor therapy are still being urgently sought. Peptide antagonists have attracted substantial attention as targeting molecules because of their high tumor accumulation and antitumor activity compared with agonists. SPA, a derivative of substance P, is a potent antagonist that exhibits antitumor activity. Based on the amino acid composition of SPA, we speculate that it can translocate across cell membranes as CPPs do. In this study, our results demonstrated that SPA could enter cells similarly to a CPP. As a vector, SPA could efficiently deliver camptothecin and plasmids into cells. In addition, our results showed that SPA exhibited low toxicity to normal cells and high enzymatic stability. Taken together, our results validated the ability of SPA for efficient drug delivery. More importantly, our study opens a new avenue for designing ideal CPPs based on peptide antagonists.

    更新日期:2020-01-13
  • Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-24
    Xianglong Yu; Huichao Wu; Haiyan Hu; Ziyi Dong; Yunni Dang; Qi Qi; Yan Wang; Shouying Du; Yang Lu

    Abstract Purpose: Maytansine (DM1) is a potent anticancer drug and limited in clinical application due to its poor water solubility and toxic side effects. Zein is widely used in nano drug delivery systems due to its good biocompatibility. In this study, we prepared DM1-loaded zein nanoparticles (ZNPs) to achieve tumor targeting and reduce toxic side effects of DM1. Methods: ZNPs were prepared by phase separation and Box-Behnken design was used to optimize the formulation. Then, confocal fluorescence microscope and flow cytometry were used to determine cellular uptake of ZNPs. A549 cells were cultured in vitro to study cytotoxicity and used to establish tumor xenografts in nude mice. Biodistribution and antitumor activity of ZNPs were performed in vivo experiments. In addition, we also performed histological and immunohistochemical examinations on tumors and viscera. Results: The optimal prescription was obtained by using 120 μL zein added to 2 mL water under stirring in 300 rpm. The encapsulation efficiency and drug loading were 82.97 ± 0.80% and 3.32 ± 0.03%, respectively. We found that DM1-loaded ZNPs have a strong inhibitory effect on A549 cells, which stemmed from the ability of ZNPs to enhance cellular uptake. Furthermore, we demonstrated that DM1-loaded ZNPs exhibits a better antitumor efficacy than DM1, which tumor inhibition rate were 97.3% and 92.7%, respectively. The biodistribution revealed that ZNPs could targeted to tumor. Finally, we confirmed by histological that DM1-loaded ZNPs are nontoxic. Conclusion: DM1-loaded ZNPs have considerable antitumor activity. Thus, DM1-loaded ZNPs are a promising treatment of non-small cell lung cancer.

    更新日期:2020-01-13
  • Mechanisms of increased bioavailability through amorphous solid dispersions: a review
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-30
    Andreas Schittny; Jörg Huwyler; Maxim Puchkov

    Abstract Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.

    更新日期:2020-01-13
  • Enhanced cytotoxicity of a redox-sensitive hyaluronic acid-based nanomedicine toward different oncocytes via various internalization mechanisms
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-02
    Yunai Du; Sheng Wang; Tianhao Zhang; Dongsheng He; Jiasheng Tu; Yan Shen

    Abstract Receptor-mediated active targeting and tumor microenvironment responsive systems from polymeric micelles have been studied for rapid cellular internalization and triggered drug release. Previously we have constructed redox-responsive polymeric micelles composed of vitamin E succinate conjugated hyaluronic acid (HA-ss-TOS), which are able to actively target CD44 proteins and quickly release loaded drugs upon exposure to high levels of glutathione (GSH) in tumor cells. In the present study, we found that despite different cellular internalization mechanisms, micelles showed strong antineoplastic effects on 4T1 and B16F10 cells due to redox responsiveness. HA-ss-TOS-PTX micelles exhibited an excellent tumor targeting ability and prolonged retention time compared to Taxol in vivo. In addition, a superior antitumor effect was achieved compared to PTX-loaded insensitive micelles (HA-TOS-PTX) and Taxol. Our results revealed that PTX-loaded HA-ss-TOS micelles could enhance the antineoplastic efficacy of PTX for breast cancer and melanoma treatment and, thus, deserve further attention.

    更新日期:2020-01-13
  • Preparation, evaluation and metabolites study in rats of novel amentoflavone-loaded TPGS/soluplus mixed nanomicelles
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-08
    Xue Feng; Yuting Chen; Luya Li; Yuqian Zhang; Lantong Zhang; Zhiqing Zhang

    Abstract Amentoflavone (AMF) is a kind of biflavonoids existing in Ginkgo biloba leaves. It has many biological activities, such as antioxidant, anti-inflammatory, anti-bacterial, antiviral, hypoglycemic, anti-tumor and inducing apoptosis. However, its solubility and bioavailability are poor and there are a few studies on it in vivo. In this study, to improve its solubility and bioavailability, the nanomicelles were prepared with TPGS and soluplus as carriers for the first time. The particle size, Zeta potential, encapsulation efficiency, drug loading, stability, cytotoxicity, cellular uptake, and metabolites in rats were studied. Cytotoxicity, cellular uptake, and metabolites in rats of AMF-loaded TPGS/soluplus mixed micelles were compared with those of AMF. As a result, AMF-loaded TPGS/soluplus mixed micelles with a particle size of 67.33 ± 2.01 nm and Zeta potential of −0.84133 ± 0.041405 mV were successfully prepared. The encapsulation efficiency and drug loading of the mixed nanomicelles were 99.18 ± 0.76% and 2.47 ± 0.01%, respectively. The physical and chemical properties of the mixed micelles were stable within 60 d, and the cytotoxicity of the mixed micelles was much greater than that of AMF monomers. Thirty-four kinds of metabolites of AMF were identified in rats. The metabolites were mainly distributed in rat feces. No metabolites were detected in bile and plasma. 14 kinds of metabolites of the mixed micelles in rats were detected, including 11 in feces, 6 in urine, and 3 in plasma, which indicated that the bioavailability of AMF has been improved. And the toxicity to cancer cells was enhanced, which laid a foundation for the development of new drugs.

    更新日期:2020-01-13
  • Minocycline-loaded PLGA electrospun membrane prevents alveolar bone loss in experimental peridontitis
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-08
    Yihui Ma; Jinlin Song; Huthayfa N. S. Almassri; Dan Zhang; Ting Zhang; Yuting Cheng; Xiaohong Wu

    Abstract Minocycline (MINO) is a tetracycline antibiotic effective against most of the bacteria microorganisms related to periodontal disease. Additionally, MINO promotes bone in vitro and in vivo. The objective of the present study was to establish the protocol for the preparation of MINO-loaded poly (lactic-co-glycolic acid) (MINO-PLGA) electrospun membranes and to evaluate their effect on osteogenesis in vitro and in a rat model of periodontitis. The characterization of MINO-PLGA electrospun membranes was assessed by scanning electron microscopy, laser scanning confocal microscopy, and contact angle measurement. The drug release study showed a sustained diffusion of MINO from electrospun membranes over a period of 40 d. The MINO-PLGA membranes containing 2% of the drug exhibited better support of osteoblast proliferation and adhesion and was subsequently used in vivo in an experimental periodontitis model. Its therapeutic potential was evaluated by the measurement of alveolar bone loss (ABL), bone volume analysis, histological analysis, and immunohistochemistry. MINO-PLGA membrane increased alveolar crest height in the periodontitis model, inhibited the expression of the ligand of the receptor activator for nuclear factor-κB (RANKL), and promoted the expression of its inhibitor, osteoprotegerin. The study demonstrated that MINO-PLGA electrospun membranes may be applied to stimulate bone regeneration in periodontitis.

    更新日期:2020-01-13
  • Study on the cellular internalization mechanisms and in vivo anti-bone metastasis prostate cancer efficiency of the peptide T7-modified polypeptide nanoparticles
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-08
    Yongwei Gu; Xinmei Chen; Haiyan Zhang; Heyi Wang; Hang Chen; Sifan Huang; Youfa Xu; Yuansheng Zhang; Xin Wu; Jianming Chen

    Abstract Bone-metastasis prostate cancer (BMPCa)-targeting gene therapy is gaining increasing concern in recent years. The peptide T7-modified polypeptide nanoparticles for delivery DNA (CRD-PEG-T7/pPMEPA1) was prepared as our previous study. However, the feasibility of CRD-PEG-T7/pPMEPA1 for BMPCa treatment, the mechanisms underlying cellular uptake, anti-BMPCa effect, and administration safety requires further research. LNCaP cells treated with endocytosis inhibitors and excessive T7 under different culture condition were carried out to investigate the mechanisms of cellular uptake of the CRD-PEG-T7-pPMEPA1. A transwell assay was applied to evaluate the cell migration ability. Besides, the tumor volume and survival rates of the PCa xenograft mice model were recorded to estimate the anti-tumor effect. In addition, the weight profiles of the PCa tumor-bearing mice, the blood chemistry, and the HE analysis of visceral organs and tumor was conducted to investigate the administration safety of CRD-PEG-T7/pPMEPA1. The results showed that PCa cellular uptake was decreased after treating with excessive free T7, endocytosis inhibitors and lower incubation temperature. Besides, CRD-PEG-T7/pPMEPA1 could inhibit the LNCaP cells chemotaxis and tumor growth. In addition, the survival duration of the PCa tumor-bearing mice treating with CRD-PEG-T7/pPMEPA1 was significantly prolonged with any systemic toxicity or damage to the organs. In conclusion, this research proposes a promising stratagem for treatment BMPCa by providing the biocompatible and effective carrier for delivery DNA therapeutic agents.

    更新日期:2020-01-13
  • OCTN2-targeted nanoparticles for oral delivery of paclitaxel: differential impact of the polyethylene glycol linker size on drug delivery in vitro, in situ, and in vivo
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-08
    Longfa Kou; Rui Sun; Shuyi Xiao; Xiao Cui; Jin Sun; Vadivel Ganapathy; Qing Yao; Ruijie Chen

    Abstract Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo. As the presence or absence of the mucus layer was the primary difference between in vitro/in situ versus in vivo, the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ, but interfered with the absorption in vivo. Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo, this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.

    更新日期:2020-01-13
  • Layer-by-layer pH-sensitive nanoparticles for drug delivery and controlled release with improved therapeutic efficacy in vivo
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-10
    Wanfu Men; Peiyao Zhu; Siyuan Dong; Wenke Liu; Kun Zhou; Yu Bai; Xiangli Liu; Shulei Gong; Shuguang Zhang

    Abstract In this work, a pH-sensitive liposome–polymer nanoparticle (NP) composed of lipid, hyaluronic acid (HA) and poly(β-amino ester) (PBAE) was prepared using layer-by-layer (LbL) method for doxorubicin (DOX) targeted delivery and controlled release to enhance the cancer treatment efficacy. The NP with pH-sensitivity and targeting effect was successfully prepared by validation of charge reversal and increase of hydrodynamic diameter after each deposition of functional layer. We further showed the DOX-loaded NP had higher drug loading capacity, suitable particle size, spherical morphology, good uniformity, and high serum stability for drug delivery. We confirmed that the drug release profile was triggered by low pH with sustained release manner in vitro. Confocal microscopy research demonstrated that the NP was able to effectively target and deliver DOX into human non-small cell lung carcinoma (A549) cells in comparison to free DOX. Moreover, the blank NP showed negligible cytotoxicity, and the DOX-loaded NP could efficiently induce the apoptosis of A549 cells as well as free DOX. Notably, in vivo experiment results showed that the DOX-loaded NPs effectively inhibited the growth of tumor, enhanced the survival of tumor-bearing mice and improved the therapeutic efficacy with reduced side-effect comparing with free drug. Therefore, the NP could be a potential intelligent anticancer drug delivery carrier for cancer chemotherapy, and the LbL method might be a useful strategy to prepare multi-functional platform for drug delivery.

    更新日期:2020-01-13
  • Synergism of cisplatin-oleanolic acid co-loaded hybrid nanoparticles on gastric carcinoma cells for enhanced apoptosis and reversed multidrug resistance
    Drug Deliv. (IF 3.829) Pub Date : 2020-01-10
    Danyang Li; Ruixue Cui; Shuning Xu; Ying Liu

    Abstract Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was core-shell structured and well-dispersed nanoparticles with size around 100 nm. The HN/CDDP/OA showed high stability and biocompatibility with pH-responsive drug release. Moreover, the CM modification in HN also demonstrated highly elevated tumor-homing nature than bare CC. Finally, the feasibility of HN/CDDP/OA in the treatment of gastric cancer (MGC-803 cell line) was assessed. HN/CDDP/OA showed better performance than mono systems with enhanced apoptosis and capable of reversing multidrug resistance (MDR) of cancer cells.

    更新日期:2020-01-13
  • Zinc oxide end-capped Fe3O4@mSiO2 core-shell nanocarriers as targeted and responsive drug delivery system for chemo-/ions synergistic therapeutics
    Drug Deliv. (IF 3.829) Pub Date : 2019-07-25
    Minchao Liu; Xiangyu Sun; Zhihui Liao; Yahui Li; Xiaoliang Qi; Yuna Qian; Hicham Fenniri; Ping Zhao; Jianliang Shen

    Abstract Multifunctional core-shell nanocarriers based on zinc oxide (ZnO)-gated magnetic mesoporous silica nanoparticles (MMSN) were prepared for cancer treatment through magnetic targeting and pH-triggered controlled drug release. Under an external magnetic field, the MMSN could actively deliver chemotherapeutic agent, daunomycin (DNM), to the targeted sites. At neutral aqueous, the functionalized MMSN could stably accommodate the DNM molecules since the mesopores were capped by the ZnO gatekeepers. In contrast, at the acid intercellular environment, the gatekeepers would be removed to control the release of drugs due to the dissolution of ZnO. Meanwhile, ZnO quantum dots not only rapidly dissolve in an acidic condition of cancer cells but also enhance the anti-cancer effect of Zn2+. An in vitro controlled release proliferation indicated that the acid sensitive ZnO gatekeepers showed well response by the ‘on-off’ switch of the pores. Cellular experiments against cervical cancer cell (HeLa cells) further showed that functionalized MMSN significantly suppressed cancer cells growth through synergistic effects between the chemotherapy and Zn2+ ions with monitoring the treatment process. These results suggested that the ZnO-gated MMSN platform is a promising approach to serve as a pH-sensitive system for chemotherapies delivery and Zn2+ controlled release for further application in the treatment of various cancers by synergistic effects.

    更新日期:2020-01-09
  • A cationic polymeric prodrug with chemotherapeutic self-sensibilization co-delivering MMP-9 shRNA plasmid for a combined therapy to nasopharyngeal carcinoma
    Drug Deliv. (IF 3.829) Pub Date : 2019-12-03
    Tao Liu, Xidong Wu, Shaohua Chen, Peina Wu, Hong Han, Hongbin Zhang, Junzheng Li, Guanxue Li, Siyi Zhang

    Abstract To obtain a high-efficiency drug and gene co-delivery system to HNE-1 tumor therapy, a polymeric prodrug (PAAs-MTX) with chemotherapeutic sensibilization was synthesized consisting of a GSH-response hyperbranched poly(amido amine) (PAAs) and an antitumor drug of methotrexate (MTX). Then, the targeting molecule to HNE-1 cells, transferrin (Tf), was conjugated to form the Tf-PAAs-MTX. This polymeric prodrug could deliver MMP-9 shRNA plasmid (pMMP-9) again to form the drug and gene co-delivery system of Tf-PAAs-MTX/pMMP-9. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency to HNE-1 cells. Besides that, Tf-PAAs-MTX also showed the chemotherapeutic sensibilization effect, the formulation containing PAAs segments showed much higher cytotoxicity than that of free MTX. Benefiting from the sensibilization effect and MTX/pMMP-9 co-delivery strategy, this Tf-PAAs-MTX/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. Moreover, its biocompatibility, especially the blood compatibility was analyzed. This polymeric prodrug provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization and targeting into one single platform, which showed a promising application in nasopharyngeal carcinoma therapy.

    更新日期:2019-12-03
  • Development of dual-targeted nano-dandelion based on an oligomeric hyaluronic acid polymer targeting tumor-associated macrophages for combination therapy of non-small cell lung cancer
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-28
    Bingjie Wang, Wei Zhang, Xiudi Zhou, Mengna Liu, Xiaoya Hou, Ziting Cheng, Daquan Chen

    Abstract In this study, the novel carrier materials were screened to structure targeting nano-micelles (named ‘nano-dandelion’) for synchronous delivery of curcumin (Cur) and baicalin (Bai), which could effectively overcome the tumor resistance. Mannose (Man) was found to bind better to CD206 receptors on the surface of tumor-associated macrophages (TAMs), thereby increasing the number of nano-dandelion engulfed by TAMs. Furthermore, oligomeric hyaluronic acid (oHA) was able to target CD44 receptors, resulting in recruitment of a higher number of nano-dandelion to locate and engulf tumor cells. The disulfide bond (S–S) in 3,3′-dithiodipropionic acid (DA) could be broken by the high concentration of glutathione (GSH) in the tumor microenvironment (TME). Based on this, we selected DA to connect hydrophobic fragments (quercetin, Que) and oHA. A reduction-sensitive amphiphilic carrier material, quercetin–dithiodipropionic acid–oligomeric hyaluronic acid–mannose–ferulic acid (Que–S–S–oHA–Man–FA; QHMF) was fabricated and synthesized by 1H NMR. Next, QHMF self-assembled into nano-dandelion, i.e. encapsulated Cur and Bai in water. Critical experimental conditions in the preparation process of nano-dandelion that could affect its final properties were explored. Nano-dandelion with a small particle size (121.0 ± 15 nm) and good normal distribution (PI = 0.129) could easily enter tumor tissue through vascular barrier. In addition, nano-dandelion with a suitable surface potential (–20.33 ± 4.02 mV) could remain stable for a long duration. Furthermore, good cellular penetration and tumor cytotoxicity of nano-dandelion were demonstrated through in vitro cellular studies. Finally, effective antitumor activity and reduced side effects were confirmed through in vivo antitumor experiments in A549 tumor-bearing nude mice.

    更新日期:2019-11-29
  • Hybrid manganese dioxide-bovine serum albumin nanostructure incorporated with doxorubicin and IR780 for enhanced breast cancer chemo-photothermal therapy
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-23
    Xiao Yuan, Yanlong Yin, Wang Zan, Xiyang Sun, Qian Yang

    Abstract The therapeutic outcome of chemotherapy is limited, although it is still the preferent strategy for cancer therapy. By regulation of tumor microenvironment and introduction of another therapeutic manner for combination therapy can enhance the anticancer activity of chemotherapeutics. Herein, we have constructed a hybrid nanostructure which composed of manganese dioxide (MnO2) and doxorubicin (DOX) as well as IR780 by stabilizing with BSA (BMDI) in one-pot procedure to alleviate tumor hypoxia and enhance tumor growth inhibition. The MnO2 can react with H2O2 to generate oxygen, and additionally react with GSH to realize tumor microenvironment responsive drug controlled release. And the release Mn ions further enhanced the magnetic resonance signal which made the BMDI a promising contrast agent for MRI. Moreover, the introduction of MnO2 has enhanced the anticancer activity of DOX in vitro and in vivo, and efficiently suppressed the tumor growth. By further introducing with photothermal therapy (PTT), the tumor growth was almost inhibited. It demonstrated that the BMDI hybrid nanostructure has great potential in tumor growth inhibition as therapeutics carrier.

    更新日期:2019-11-26
  • Preparation and study of two kinds of ophthalmic nano-preparations of everolimus
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-21
    Zhan Tang, Lina Yin, Yawen Zhang, Wenying Yu, Qiao Wang, Zhajun Zhan

    Abstract Objective: To prepare everolimus nanoformulations and increase their solubility to suit their application in the eye. Methods: The everolimus micelles was prepared by thin film dispersion method using Tween-80 (P80) and polyoxyethylene stearate (P40S) as carriers. In addition, the everolimus nanosuspension was prepared by injection method using poloxamer 407 (P407), hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) as stabilizers. It was characterized in terms of particle size, PDI and encapsulation efficiency or drug loading. The in vitro release and in vitro rabbit scleral permeability characteristics were investigated, and the pharmacokinetics of anterior chamber drug in rabbit eyes were studied. Results: The average particle size of the micelles was (8.74 ± 0.21) nm, the encapsulation efficiency and drug loading were (90.12 ± 1.18)% and (2.14 ± 0.028)%, while the average particle size of the nanosuspension was (156.47 ± 1.10) nm, and the drug loading was (16.51 ± 0.21)%, respectively. Both in vitro release and rabbit scleral permeation models were consistent with the Higuchi equation. The pharmacokinetic experiments of aqueous humor showed that area under the curve of everolimus nanosuspension was about 3 times higher than that of micelles. Micelles could be achieved in the eye and maintained for a long time. Conclusion: The preparation of everolimus micelles or nanosuspension for eye are suitable for ocular administration and expected to be new dosage form for corneal transplantation immunological rejection or other ocular disease.

    更新日期:2019-11-22
  • Enhancement of zaleplon oral bioavailability using optimized self-nano emulsifying drug delivery systems and its effect on sleep quality among a sample of psychiatric patients
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-21
    Maha K. A. Khalifa, Hoda A. Salem, Seham M. Shawky, Heba A. Eassa, Asmaa M. Elaidy

    Abstract The aim of this work is to develop self-nano emulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of zaleplon (Zal) as a poorly water-soluble drug. Moreover, the bioavailability and the effect on the quality of sleep among a sample of psychiatric patients is to be assessed. D-optimal mixture design was used for optimization. Optimized SNEDDS formulation was evaluated for droplet size, transmission electron microscope (TEM) and in-vitro dissolution test. Zal bioavailability was evaluated by determining its serum concentration and pharmacokinetic parameters in 8 patients after oral administration. Effect on sleep quality was assessed among 40 psychiatric patients. Patients’ sleep quality was assessed in 40 psychiatric patients before and after medication using the Arabic version of the Pittsburgh Sleep Quality Index (PSQI). Zal- SNEDDS appeared as nano-sized spherical vesicles. Moreover, Zal was completely dissolved from optimized formulation after 45 min indicating improved dissolution rate. Zal-SNEDDS showed significantly higher Cmax, Tmax and AUC0→∞ compared to commercial product after oral administration. Zal-SNEDDS significantly improved the total score of PSQIs (p < .001) with higher subjective sleep quality, reduced sleep latency, improved day time function and sleep disturbance (p < .001). Using sleep medication was reduced significantly (p = .027). However, it did not modify sleep duration or sleep efficiency. SNEDDS have improved Zal solubility and enhanced its bioavailability. Furthermore, Zal-SNEDDS have improved the total score of PSQIs and may be considered a good choice to enhance the quality of sleep among psychiatric patients.

    更新日期:2019-11-22
  • Optimized nonionic emulsifier for the efficient delivery of astaxanthin nanodispersions to retina: in vivo and ex vivo evaluations
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-21
    Lei Xu, Haixiang Yu, Hongbin Sun, Xiang Yu, Ye Tao

    Abstract Astaxanthin (AST) is a naturally occurring carotenoid with potent anti-oxidative and anti-inflammatory potency against chronic diseases. In this study, we suspended AST in different nonionic emulsifiers to produce nanodispersions. The basic physicochemical properties of the produced AST nanodispersions were verified to select the optimized nonionic emulsifier. Among the tested emulsifiers, Polysorbate 20 produced the AST nanoemulsions with smaller particle diameters, narrower size distributions, and higher AST contents among these emulsifiers. The N-methyl-N-nitrosourea (MNU) administered mouse is a chemically induced retinal degeneration (RD) model with rapid progress rate. AST suspended in Polysorbate 20 was demonstrated to ameliorate the dramatic consequences of MNU on retina architectures and function in several different tests encompassing from electrophysiology to histology and molecular tests. Furthermore, the multi-electrodes array (MEA) was used to detect the firing activities of retinal ganglion cells within the inner retinal circuits. We found that AST nanodispersions could restrain the spontaneous firing response, enhance the light induced firing response, and preserve the basic configurations of visual signal pathway in degenerative retinas. The MEA assay provided an appropriate example to evaluate the potency of pharmacological compounds on retinal plasticity. In summary, emulsifier type affects the basic physicochemical characteristic of AST nanodispersions. Polysorbate 20 acts as an optimized nonionic emulsifier for the efficient delivery of AST nanodispersions to retina. AST nanodispersions can alleviate the photoreceptor loss and rectify the abnormities in visual signal transmission.

    更新日期:2019-11-21
  • Nanoparticles for antiparasitic drug delivery
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-20
    Yuzhu Sun, Dongmei Chen, Yuanhu Pan, Wei Qu, Haihong Hao, Xu Wang, Zhenli Liu, Shuyu Xie

    Abstract As an emerging novel drug carrier, nanoparticles provide a promising way for effective treatment of parasitic diseases by overcoming the shortcomings of low bioavailability, poor cellular permeability, nonspecific distribution and rapid elimination of antiparasitic drugs from the body. In recent years, some kinds of ideal nanocarriers have been developed for antiparasitic drug delivery. In this review, the progress of the enhanced antiparasitic effects of different nanoparticles payload and their influencing factors were firstly summarized. Secondly, the transport and disposition process in the body were reviewed. Finally, the challenges and prospects of nanoparticles for antiparasitic drug delivery were proposed. This review will help scholars to understand the development trend of nanoparticles in the treatment of parasitic diseases and explore strategies in the development of more efficient nanocarriers to overcome the difficulty in the treatment of parasite infections in the future.

    更新日期:2019-11-20
  • (-)-Epigallocatechin-3-gallate encapsulated realgar nanoparticles exhibit enhanced anticancer therapeutic efficacy against acute promyelocytic leukemia
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Wei Fang, Zhao Liang Peng, Ya Ji Dai, Dian Lei Wang, Peng Huang, He Ping Huang

    Abstract Realgar and (-)-Epigallocatechin-3-gallate (EGCG) are natural medicines that inhibit cancer cell growth, resulting in inhibition of formation and development of tumors. The anticancer effects of realgar and EGCG were greatly improved following formulation as nanoparticles. EGCG has received increased attention as a drug carrier. The aim of this study was to prepare a new nanomedicine, (EGCG-RNPs), in which encapsulated nano-realgar. EGCG-RNPs were prepared by coprecipitation and characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), particle size and zeta potential, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and in vitro release. Furthermore, we evaluated the antiproliferative effects of EGCG-RNPs on HL-60 cells in vitro, antitumor effect by intratumoral injection of EGCG-RNPs into solid tumors derived from APL HL-60 cells in vivo. Possible mechanisms were evaluated using uptake and efflux experiments in HL-60 cells. The results showed that the average particle size and zeta potentials of EGCG-RNPs was 200.3 ± 1.23 nm and −46.8 ± 1.31 mV. Controlled release of EGCG-RNPs was sustained and continued up to 72 h in vitro. Compared with nano-realgar and EGCG + RNPs (EGCG and nano-realgar physical mixing), EGCG-RNPs significantly inhibited growth of HL-60 cells. In a solid tumor model, EGCG-RNPs decreased tumor volumes, with an inhibitory rate of 60.18% at a dose of 70 mg · kg−1. The mechanisms of antitumor improvement may correlate with the increased uptake of realgar and prolonged the retention time of realgar in HL-60 cells due to EGCG as a carrier. EGCG-RNPs could enhance anticancer therapeutic efficacy for acute promyelocytic leukemia.

    更新日期:2019-11-18
  • Redox-sensitive lipophilic prodrugs: delivering unstable chemotherapeutant for improved cancer therapy
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Fu Li, Zhao Huang, Huitong Chen, Lu Yan, Jin Li, Yue Su, Qian Zhang, Zhengye Huang, Yaxin Zheng

    Abstract Therapeutic application of unmodified camptothecin (CPT) is severely restricted by its extremely low water solubility and the instability of active lactone ring. In this study, a redox-sensitive CPT-OA conjugate containing the disulfide bond (CPT-SS-OA) was used to deliver the lactone-stabilized CPT for the improved antitumor efficacy. A non-sensitive CPT-OA was used as control to illuminate the role of disulfide bond. Both CPT-SS-OA and CPT-OA formulated in cremophor EL micelles (CM) displayed multiple therapeutic advantages: small diameter (∼14 nm), efficient cellular internalization, prolonged blood circulation, and favorable biodistribution. However, only CPT-SS-OA/CM achieved the superior chemotherapeutic efficacy over CPT solution in the Lewis lung carcinoma (LLC) cancer xenograft, which was ascribed to the accelerated release of the active lactone CPT responding to the elevated reductive glutathione in tumor cells. Such redox-sensitive lipophilic prodrugs represent an effective alternative strategy for the delivery of CPT in the active lactone form. This strategy can be used for other chemically unstable chemotherapeutant for the improved therapeutic efficacies.

    更新日期:2019-11-18
  • Co-delivery of plantamajoside and sorafenib by a multi-functional nanoparticle to combat the drug resistance of hepatocellular carcinoma through reprograming the tumor hypoxic microenvironment
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Ying Zan, Zhijun Dai, Liang Liang, Yujiao Deng, Lei Dong

    Abstract Sorafenib (SOR) is a multi-kinase inhibitor that was approved as the first-line systematic treatment agent of hepatocellular carcinoma (HCC). However, the anti-cancerous effect of SOR is dramatically impaired by the drug resistance, insufficient accumulation at tumor tissues, and limited tumor inner penetration. To combat the above issues, the PLA-based nanoparticles were first fabricated and co-loaded with SOR and plantamajoside (PMS), natural herbal medicines that possess excellent anti-cancerous effect on many types of drug resistant cancers. Then, the polypeptide CT, which is tumor-homing and cell membrane penetrable, was further decorated on the dual-agents loaded nanoparticles (CTNP-PMS/SOR) to enhance tumor accumulation of drugs. Importantly, the CT peptide is a conjugate derived from the covalent conjugation of CVNHPAFAC peptide, a tumor-homing peptide, on the fourth lysine of TAT, namely cell membrane penetrating peptide, through a pH-sensitive hydrazone bond. By this way, the cell penetrating ability of TAT was dramatically sealed under the normal condition and immediately recovered once the nanoparticles reached tumor sites. Both in vivo and in vitro experiments demonstrated that the anti-cancerous effect of SOR on malignant HCC was significantly enhanced after co-loaded with PMS. Mechanisms studies revealed that the PMS is capable of reprograming the tumor hypoxic microenvironment, which represents the main cause of drug-resistance of tumor cells. Besides, functionalization of the NP-PMS/SOR with CT peptides signally improved the accumulation of drugs at tumor sites and penetration of agents into tumor cells, which in turn resulted in stronger capacity of tumor growth inhibition.

    更新日期:2019-11-18
  • Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Tao Liu, Xinxin Yu, Haipeng Yin, Jan P. Möschwitzer

    Abstract Drug nanosuspensions/nanocrystals have been recognized as one useful and successful approach for drug delivery. Drug nanocrystals could be further decorated to possess extended functions (such as controlled release) and designed for special in vivo applications (such as drug tracking), which make best use of the advantages of drug nanocrystals. A lot of novel and advanced size reduction methods have been invented recently for special drug deliveries. In addition, some novel downstream processes have been combined with nanosuspensions, which have highly broadened its application areas (such as targeting) besides traditional routes. A large number of recent research publication regarding as nanocrystals focuses on above mentioned aspects, which have widely attracted attention. This review will focus on the recent development of nanocrystals and give an overview of regarding modification of nanocrystal by some new approaches for tailor-made drug delivery.

    更新日期:2019-11-18
  • Eprinomectin nanoemulgel for transdermal delivery against endoparasites and ectoparasites: preparation, in vitro and in vivo evaluation
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Yujuan Mao, Xiaolan Chen, Bohui Xu, Yan Shen, Zixuan Ye, Birendra Chaurasiya, Li Liu, Yi Li, Xiaoling Xing, Daquan Chen

    Abstract Nanoemulgels are composed of O/W nanoemulsion and hydrogels and are considered as ideal carriers for the transdermal drug delivery because these have high affinity to load hydrophobic drugs. The stable formulation of eprinomectin (EPR) is very challenging because of it is high hydrophobic nature. In this work, we have prepared EPR loaded nanoemulgel for the treatment of endo- and ectoparasites. The surface morphology of optimized formulations was characterized by scanning electron microscopy. Additionally, skin permeability and irritation tests were conducted for in vitro safety and in vivo skin retention and pearmeation test of EPR nanoemulgel were conducted for efficacy study. Obtained results indicated that the optimized formulation had good shear-thinning behavior, bioadhesiveness properties, and are nanosized droplets with porous internal structure, which are required for topical application. Furthermore, this formulation has showed good skin permeability in comparison to suspension and has no skin irritating property. Overall, the obtained results proved that nanoemulgel is a promising carrier for transdermal drug delivery and EPR nanoemulgel is a promising formulation for the treatment of endo- and ectoparasites.

    更新日期:2019-11-18
  • A novel adjuvant drug-device combination tissue scaffold for radical prostatectomy
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Ketevan Paliashvili, Francesco Di Maggio, Hei Ming Kenneth Ho, Sanjayan Sathasivam, Hashim Ahmed, Richard M. Day

    Abstract Prostate cancer is a leading cause of death in men and despite improved surgical procedures that aid tumor resection, the risk of recurrence after surgery as a result of positive resection margins remains significant. Adjuvant chemotherapy is often required but this is associated with toxicity. Improved ways of delivering highly toxic chemotherapeutic drugs in a more controlled and targeted manner after the prostate has been removed during surgery could reduce the risk of recurrence and avoid systemic toxicity. The aim of this study was to develop a novel drug-device combination tissue scaffold that can be used to deliver the chemotherapeutic agent, docetaxel, into the tissue cavity that is created following radical prostatectomy. The device component investigated consisted of highly porous, poly(dl-lactide-co-glycolide) microparticles made using thermally induced phase separation. A facile method was established for loading docetaxel with high efficiency within one hour. Sustained drug release was observed from the microparticles when placed into a dynamic system simulating tissue perfusion. The drug released from the microparticles into perfusates collected at regular time intervals inhibited colony formation and exhibited sustained cytotoxicity against 3D spheroids of PC3 prostate cancer cells over 10 days. In conclusion, this study demonstrates the concept of combining docetaxel with the biodegradable microparticles at the point of care is technically feasible for achieving an effective drug-device combination tissue scaffold. This approach could provide an effective new approach for delivering adjuvant chemotherapy following radical prostatectomy.

    更新日期:2019-11-18
  • Novel mitochondrial targeting charge-reversal polysaccharide hybrid shell/core nanoparticles for prolonged systemic circulation and antitumor drug delivery
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Lei Fang, Wei Zhang, Zhen Wang, Xinxin Fan, Ziting Cheng, Xiaoya Hou, Daquan Chen

    Abstract Stability in systemic circulation, effective tumor accumulation, and the subsequent crucial subcellular targeting are significant elements that maximize the therapeutic efficacy of a drug. Accordingly, novel nanoparticles based on polysaccharides that simultaneously presented prolonged systemic circulation and mitochondrial-targeted drug release were synthesized. First, the mitochondrial-targeted polymer, 3,4-dihydroxyphenyl propionic acid-chitosan oligosaccharide-dithiodipropionic acid-berberine (DHPA-CDB), was synthesized, which was used to form self-assembled curcumin (Cur)-encapsulated cationic micelles (DHPA-CDB/Cur). Negatively charged oligomeric hyaluronic acid-3-carboxyphenylboronic acid (oHA-PBA), a ligand to sialic acid and CD44, was further added to the surface of the preformed DHPA-CDB/Cur core to shield the positive charges and to prolong blood persistence. oHA-PBA@DHPA-CDB/Cur formed a covalent polyplex of oHA-PBA and DHPA-CDB/Cur via the pH-responsive borate ester bond between PBA and DHPA. The mildly acidic tumor environment led to the degradation of borate ester bonds, thereby realizing the exposure of the cationic micelles and causing a charge reversal from −19.47 to +12.01 mV, to promote cell internalization and mitochondrial localization. Compared with micelles without the oHA-PBA modification, the prepared oHA-PBA@DHPA-CDB/Cur showed enhanced cytotoxicity to PANC-1 cells and greater cellular uptake via receptor-mediated endocytosis. oHA-PBA@DHPA-CDB/Cur was effectively targeted to the mitochondria, which triggered mitochondrial membrane depolarization. In mice xenografted with PANC-1 cells, compared with control mice, oHA-PBA@DHPA-CDB/Cur resulted in more effective tumor suppression and greater biosafety with preferential accumulation in the tumor tissue. Thus, the long-circulating oHA-PBA@DHPA-CDB/Cur, with mitochondrial targeting and tumor environment charge-reversal capabilities, was shown to be an excellent candidate for subcellular-specific drug delivery.

    更新日期:2019-11-18
  • Transdermal delivery of fluvastatin sodium via tailored spanlastic nanovesicles: mitigated Freund's adjuvant-induced rheumatoid arthritis in rats through suppressing p38 MAPK signaling pathway
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Shahira F. El Menshawe, Mohamed M. Nafady, Heba M. Aboud, Rasha M. Kharshoum, Asmaa Mohammed M. Hussein Elkelawy, Doaa S. Hamad

    Abstract The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (24). Applying Design-Expert® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm2). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.

    更新日期:2019-11-18
  • Mechanisms of oral absorption improvement for insoluble drugs by the combination of phospholipid complex and SNEDDS
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Yingpeng Tong, Qin Zhang, Wen Shi, Jianxin Wang

    Abstract In the present study, a water insoluble drug named silybin was encapsulated into self-nanoemulsifying drug delivery system (SNEDDS) following the preparation of silybin–phospholipid complex (SB–PC), then several methods were carried out to characterize SB–PC–SNEDDS and elucidate its mechanisms to improve the oral absorption of SB. Using a dynamic in vitro digestion model, the lipolysis of SB–PC–SNEDDS was proved to be mainly related with the property of its lipid excipients. SB–PC–SNEDDS could significantly enhance the transport of SB across Caco-2 cells, which may partly attribute to the increased cell membrane fluidity and the loss of tight junction according to the analysis results of fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and tight junction protein (ZO-1). The result of in situ perfusion showed the intestinal absorption of SB from high to low was SB–PC–SNEDDS, SB–PC, and SB. The extent of lymphatic transport of SB–PC and SB–PC–SNEDDS via the mesenteric duct was 12.2 and 22.7 folds of that of SB, respectively. In the lymph duct cannulated rats, the relative bioavailability (Fr) of SB–PC and SB–PC–SEDDS compared to SB was 1265.9% and 1802.5%, respectively. All the above results provided mechanistic support for oral absorption improvement of water insoluble drugs by the combination of PC and SNEDDS.

    更新日期:2019-11-18
  • Preparation and in vivo evaluation of a highly skin- and nail-permeable efinaconazole topical formulation for enhanced treatment of onychomycosis
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Byung Chul Lee, Rudra Pangeni, Jungtae Na, Kyo-Tan Koo, Jin Woo Park

    Abstract Onychomycosis is a progressive fungal infection of the nails that involves the deeper nail layer and nail bed. It is important to maintain sufficient drug concentration in the diseased tissues after topical application. In this study, a stable topical delivery system for efinaconazole (EFN) was designed to enhance absorption potential through the skin and nail plate by incorporating ethanol, diethylene glycol monoethyl ether (Transcutol P) and isopropyl myristate, and cyclomethicone into the topical solution as a delivery vehicle, permeation enhancers, and a wetting agent, respectively. In addition, the stability of EFN in the formulation was significantly improved by adding butylated hydroxytoluene, diethylenetriamine pentaacetic acid, and citric acid as an antioxidant, chelating agent, and pH-adjusting agent, respectively, without discoloration. The optimum EFN formulation (EFN-K) showed 1.46-fold greater human skin permeation than that of the reference control (commercial 10% EFN topical solution). Furthermore, after a 24-hour incubation, the amount of infiltrated EFN from EFN-K in the human nail plate was 4.11-fold greater than that of the reference control, resulting in an 89.7% increase in nail flux at 7 days after treatment. EFN-K significantly accelerated structural recovery of the keratin layer in a Trichophyton mentagrophytes-infected guinea pig onychomycosis model, decreasing the mean viable fungal cell count by 54.3% compared to the vehicle-treated group after once-daily treatment for 4 weeks. Thus, the accelerated skin and nail penetration effect of EFN-K is expected to achieve good patient compliance, and improve the complete cure rate of onychomycosis.

    更新日期:2019-11-18
  • Uniform-sized insulin-loaded PLGA microspheres for improved early-stage peri-implant bone regeneration
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Xing Wang, Feng Qi, Helin Xing, Xiaoxuan Zhang, Chunxiang Lu, Jiajia Zheng, Xiuyun Ren

    Abstract Poor initial stability at the first four weeks after surgery is becoming the major causes for metal implant failure. Previous attempts neglected the control release of insulin for the bone regeneration among nondiabetic subjects. The major reason may lie in the adverse effects, such as attenuated bone formation, hypoglycemia or hyperinsulinemia, that caused by the excessive insulin. Thus, spatiotemporal release of insulin may serve as the promising strategy. To address this, through solvent extraction (EMS), solvent evaporation (SMS) and cosolvent methods (CMS), we prepared three types of PLGA microspheres with various internal structures, but similar size distribution. The effects of the preparation methods on the properties of the microspheres, such as their release behavior, degradation of molecular weight, and structural evolution, were investigated. Human bone marrow mesenchymal stromal cells (BMSCs) and rabbit implant models were used to test the bioactivity of the microspheres in vitro and in vivo, respectively. The result demonstrated that these three preparation methods did not influence the polymer degradation but instead affected the internal structural evolution, which plays a crucial role in the release behavior, osteogenesis and peri-implant bone regeneration. Compared with EMS and CMS microspheres, SMS microspheres exhibited a relatively steady release rate in the first four weeks, which evidently stimulated the osteogenic differentiation of the stem cells and peri-implant bone regeneration. Meanwhile, SMS microspheres significantly enhanced the stability of the implant at Week 4, which is promising to reduce early failure rate of the implant without inducing adverse effects on the serum biochemical indices.

    更新日期:2019-11-18
  • Oral delivery of lycopene-loaded microemulsion for brain-targeting: preparation, characterization, pharmacokinetic evaluation and tissue distribution
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-18
    Yunliang Guo, Xuyan Mao, Jing Zhang, Peng Sun, Haiyang Wang, Yue Zhang, Yingjuan Ma, Song Xu, Renjun Lv, Xueping Liu

    Abstract Lycopene is considered as a promising neuroprotector with multiple bioactivities, while its therapeutic use in neurological disorders is restricted due to low solubility, instability and limited bioavailability. Our work aimed to develop lycopene-loaded microemulsion (LME) and investigate its potentials in improving bioavailability and brain-targeting efficiency following oral administration. The blank microemulsion (ME) excipients were selected based on orthogonal design and pseudo-ternary phase diagrams, and LME was prepared using the water titration method and characterized in terms of stability, droplet size distribution, zeta potential, shape and lycopene content. The optimized LME encompassed lycopene, (R)-(+)-limonene, Tween 80, Transcutol HP and water and lycopene content was 463.03 ± 8.96 µg/mL. This novel formulation displayed transparent appearance and satisfactory physical and chemical stabilities. It was spherical and uniform in morphology with an average droplet size of 12.61 ± 0.46 nm and a polydispersity index (PDI) of 0.086 ± 0.028. The pharmacokinetics and tissue distributions of optimized LME were evaluated in rats and mice, respectively. The pharmacokinetic study revealed a dramatic 2.10-fold enhancement of relative bioavailability with LME against the control lycopene dissolved in olive oil (LOO) dosage form in rats. Moreover, LME showed a preferential targeting distribution of lycopene toward brain in mice, with the value of drug targeting index (DTI) up to 3.45. In conclusion, the optimized LME system demonstrated excellent physicochemical properties, enhanced oral bioavailability and superior brain-targeting capability. These findings provide a basis for the applications of ME-based strategy in brain-targeted delivery via oral route, especially for poorly water-soluble drugs.

    更新日期:2019-11-18
  • Dual functional matrix metalloproteinase-responsive curcumin-loaded nanoparticles for tumor-targeted treatment
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-06
    Fangyuan Guo, Qiafan Fu, Chenhao Jin, Xugang Ji, Qinying Yan, Qingliang Yang, Danjun Wu, Ying Gao, Weiyong Hong, Aiqin Li, Gensheng Yang

    Abstract The limitations of anticancer drugs, including poor tumor targeting and weak uptake efficiency, are important factors affecting tumor therapy. According to characteristics of the tumor microenvironment, in this study, we aimed to synthesize matrix metalloproteinase (MMP)-responsive curcumin (Cur)-loaded nanoparticles (Cur-P-NPs) based on amphiphilic block copolymer (MePEG-peptide-PET-PCL) with MMP-cleavable peptide (GPLGIAGQ) and penetrating peptide (r9), modified to improve tumor targeting and cellular uptake. The average size of Cur-P-NPs was 176.9 nm, with a zeta potential of 8.1 mV, and they showed drug entrapment efficiency and a loading capacity of 87.07% ± 0.63% and 7.44% ± 0.16%, respectively. Furthermore, Cur release from Cur-P-NPs was sustained for 144 h at pH 7.4, and the release rate was accelerated under enzyme reaction condition. The MTT assay demonstrated that free P-NPs had favorable biosafety, and the anti-proliferative activity of Cur-P-NPs was positively correlated with Cur concentration in MCF-7 cells. Additionally, the results of cellular uptake, in vivo pharmacokinetics, and biodistribution showed that Cur-P-NPs had a good effect on cellular uptake and tumor targeting, resulting in the best bioavailability in tumor therapy. Therefore, Cur-P-NPs, as a promising drug delivery system, might lead to a new and efficient route for targeted therapy in clinical practice.

    更新日期:2019-11-06
  • Active pulmonary targeting against tuberculosis (TB) via triple-encapsulation of Q203, bedaquiline and superparamagnetic iron oxides (SPIOs) in nanoparticle aggregates
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-06
    Wilson Poh, Nurlilah Ab Rahman, Yan Ostrovski, Josué Sznitman, Kevin Pethe, Say Chye Joachim Loo

    Abstract Tuberculosis (TB) has gained attention over the past few decades by becoming one of the top ten leading causes of death worldwide. This infectious disease of the lungs is orally treated with a medicinal armamentarium. However, this route of administration passes through the body’s first-pass metabolism which reduces the drugs’ bioavailability and toxicates the liver and kidneys. Inhalation therapy represents an alternative to the oral route, but low deposition efficiencies of delivery devices such as nebulizers and dry powder inhalers render it challenging as a favorable therapy. It was hypothesized that by encapsulating two potent TB-agents, i.e. Q203 and bedaquiline, that inhibit the oxidative phosphorylation of the bacteria together with a magnetic targeting component, superparamagnetic iron oxides, into a poly (D, L-lactide-co-glycolide) (PDLG) carrier using a single emulsion technique, the treatment of TB can be a better therapeutic alternative. This simple fabrication method achieved a homogenous distribution of 500 nm particles with a magnetic saturation of 28 emu/g. Such particles were shown to be magnetically susceptible in an in-vitro assessment, viable against A549 epithelial cells, and were able to reduce two log bacteria counts of the Bacillus Calmette-Guerin (BCG) organism. Furthermore, through the use of an external magnet, our in-silico Computational Fluid Dynamics (CFD) simulations support the notion of yielding 100% deposition in the deep lungs. Our proposed inhalation therapy circumvents challenges related to oral and respiratory treatments and embodies a highly favorable new treatment regime.

    更新日期:2019-11-06
  • Local penetration of doxorubicin via intrahepatic implantation of PLGA based doxorubicin-loaded implants
    Drug Deliv. (IF 3.829) Pub Date : 2019-11-06
    Li Gao, Qingshan Li, Jie Zhang, Yixin Huang, Lin Deng, Chenyang Li, Guangping Tai, Banfeng Ruan

    Abstract Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.

    更新日期:2019-11-06
  • Correction.
    Drug Deliv. (IF 3.829) Pub Date : null

    更新日期:2019-11-01
  • Novel polyethyleneimine-R8-heparin nanogel for high-efficiency gene delivery in vitro and in vivo.
    Drug Deliv. (IF 3.829) Pub Date : 2017-12-22
    Linjiang Song,Xiuqi Liang,Suleixin Yang,Ning Wang,Tao He,Yan Wang,Lan Zhang,Qinjie Wu,Changyang Gong

    Gene therapy is an efficient and promising approach to treat malignant tumors. However, protecting the nucleic acid from degradation in vivo and efficient delivering it into tumor cells remain challenges that require to be addressed before gene therapy could be applied in clinic. In this study, we prepared novel polyethyleneimine-RRRRRRRR(R8)-heparin (HPR) nanogel as an efficient gene delivery system, which consists of heparin and cell penetrating peptide R8 grafted low-molecule-weight polyethyleneimine (PEI). Due to the shielding effect of heparin, crosslinking PEI-R8 with heparin was designed to diminish the toxicity of the gene delivery system. Meanwhile, a partial of R8 peptide which located on the surface of HPR nanogel could significantly enhance the cellular uptake. The formed HPR/pDNA complex exhibited effective endolysosomal escape, resulting in a high-efficiency transfection. Furthermore, the HPR could deliver the plasmid which could transcribe human TNF-related apoptosis inducing ligand (phTRAIL), into HCT-116 cells and induce significant cell apoptosis. In addition, HPR/phTRAIL complex showed satisfactory antitumor activity in abdominal metastatic colon carcinoma model. Finally, the antitumor mechanism of HPR/phTRAIL was also explored by western blot and histological analysis. The above results suggested that the HPR nanogel could serve as a promising gene delivery system.

    更新日期:2019-11-01
  • Repaglinide-loaded nanostructured lipid carriers with different particle sizes for improving oral absorption: preparation, characterization, pharmacokinetics, and in situ intestinal perfusion.
    Drug Deliv. (IF 3.829) Pub Date : null
    Lei Wu,Lin Zhao,Xitong Su,Peng Zhang,Guixia Ling

    Repaglinide-loaded nanostructured lipid carriers (REP-NLCs) with different particle sizes were successfully designed and prepared to investigate the permeation and absorption ability by in situ single-pass intestinal perfusion (SPIP) study and pharmacokinetics. Both of the formulations prepared by solvent diffusion method exhibited a spherical shape under transmission electron microscopy (TEM) and similar zeta potential value of -11 mV. The particles size, encapsulation efficiency (EE), drug loading (DL) of REP-NLCs-Small and REP-NLCs-Large size preparations were about 79 nm and 325 nm, 96.83% and 98.60%, 4.41% and 3.05%, respectively. Besides, both REP-NLCs showed good colloidal stability and had no burst release phenomenon compared with REP-Sol. SPIP demonstrated the improved membrane permeability for NLCs compared with REP-Sol, especially NLCs-Small size preparation. The bioavailability increased sequentially in REP-Sol, REP-NLCs-Large, and REP-NLCs-Small, and the difference between each other was statistical significant. Our investigations demonstrate that NLCs with small particles size of 50-100 nm, such as 79 nm, are able to enhance absorption performance of a poorly soluble repaglinide compared with large particles size, such as 325 nm, by significantly improving the absorption in jejunum, and colon of rats and thus well improving oral bioavailability.

    更新日期:2019-11-01
  • Correction.
    Drug Deliv. (IF 3.829) Pub Date : null

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Co-delivery of deferoxamine and hydroxysafflor yellow A to accelerate diabetic wound healing via enhanced angiogenesis.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-20
    Si-Qian Gao,Chen Chang,Jun-Jun Li,Ying Li,Xiao-Qian Niu,Dan-Ping Zhang,Long-Jian Li,Jian-Qing Gao

    Nonhealing chronic wounds on foot induced by diabetes is a complicated pathologic process. They are mainly caused by impaired neovascularization, neuropathy, and excessive inflammation. A strategy, which can accelerate the vessel network formation as well as inhibit inflammatory response at the same time, makes it possible for effective diabetic ulcers treatment. Co-delivery of multiple drugs with complementary bioactivity offers a strategy to properly treat diabetic wound. We previously demonstrated that hydroxysafflor yellow A (HSYA) could accelerate diabetic wound healing through promoting angiogenesis and reducing inflammatory response. In order to further enhance blood vessel formation, a pro-angiogenic molecular called deferoxamine (DFO) was topically co-administrated with HSYA. The in vitro results showed that the combination of DFO and HSYA exerted synergistic effect on enhancing angiogenesis by upregulation of hypoxia inducible factor-1 alpha (HIF-1α) expression. The interpenetrating polymer networks hydrogels, characterized by good breathability and water absorption, were designed for co-loading of DFO and HSYA aiming to recruit angiogenesis relative cells and upgrade wound healing in vivo. Both DFO and HSYA in hydrogel have achieved sustained release. The in vivo studies indicated that HSYA/DFO hydrogel could accelerate diabetic wound healing. With a high expression of Hif-1α which is similar to that of normal tissue. The noninvasive US/PA imaging revealed that the wound could be recovered completely with abundant blood perfusion in dermis after given HSYA/DFO hydrogel for 28 days. In conclusion, combination of pro-angiogenic small molecule DFO and HSYA in hydrogel provides a promising strategy to productively promote diabetic wound healing as well as better the repair quality.

    更新日期:2019-11-01
  • Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-20
    Anne Clavreul,Emilie Roger,Milad Pourbaghi-Masouleh,Laurent Lemaire,Clément Tétaud,Philippe Menei

    Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drug payload of 2.11 ± 0.03 mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potential of LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.

    更新日期:2019-11-01
  • Borneol and Α-asarone as adjuvant agents for improving blood-brain barrier permeability of puerarin and tetramethylpyrazine by activating adenosine receptors.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-20
    Jun-Yong Wu,Yong-Jiang Li,Le Yang,Yi-Yun Hu,Xiong-Bin Hu,Tian-Tian Tang,Jie-Min Wang,Xin-Yi Liu,Da-Xiong Xiang

    Puerarin (PUE) and tetramethylpyrazine (TMP) are central nervous system (CNS) drugs used in cerebrovascular diseases. Poor brain-blood barrier (BBB) permeability limited their clinical application. Borneol and α-asarone have been proposed as an oral brain-targeting enhancer. In this study, we aimed to first evaluate the 'orifice-opening' effect of borneol and α-asarone, both aromatic resuscitation drugs, on improvement of brain delivery of PUE and TMP and second to investigate whether the enhancing effects were associated with adenosine receptors (ARs)-mediated trans-BBB pathway. In vitro BBB model was established and borneol and α-asarone significantly increased the cumulative amount of permeated PUE and TMP and the enhancing effects could be counteracted by AR inhibitors. Borneol and α-asarone could decrease expression of ZO-1, an important BBB junction protein, but inversely increase the expression of A1AR and A2AAR. In vivo pharmacokinetic study also confirmed that oral co-administration of borneol or α-asarone significantly increased AUCbrain for PUE and TMP. These results suggested that borneol and α-asarone are both effective adjuvant agents for delivery of PUE and TMP to the brain.

    更新日期:2019-11-01
  • A novel redox/pH dual-responsive and hyaluronic acid-decorated multifunctional magnetic complex micelle for targeted gambogic acid delivery for the treatment of triple negative breast cancer.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-20
    Mang Mang Sang,Fu Lei Liu,Yang Wang,Ren Jie Luo,Xiao Xian Huan,Ling Fei Han,Zhong Tao Zhang,Feng Feng,Wei Qu,Wenyuan Liu,Feng Zheng

    Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor biocompatibility. In the present study, a novel of redox/pH dual-responsive multifunctional magnetic complex micelle (sPEG/HA/CSO-SS-Hex/Fe3O4/GA), which consisted of a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and DCA grafted sheddable PEG-PLL (sPEG) copolymers and loaded with gambogic acid (GA) and Fe3O4 nanoparticles were developed for parenteral delivery for the treatment of triple negative breast cancer (TNBC). The ex vivo study showed that the sPEG shielded cationic HA/CSO-SS-Hex/Fe3O4/GA core at physiological pH but quickly shed off to re-expose the core due to its charge reversible property. The sPEG/HA/CSO-SS-Hex/Fe3O4/GA micelles effectively facilitated tumor-targeted GA delivery by HA, which is a targeting ligand for CD44 receptor of TNBC cells, meanwhile increase GA uptake at the acidic condition but diminished the drug uptake at neutral pH. The in vitro cellular uptake study and in vivo biodistribution and antitumor activity of the formulations were determined, all results showed that the complex micelle enhanced TNBC tumor cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox/pH dual-responsive drug release. Hence, tumor-targeted delivery of GA with redox/pH dual-responsive multifunctional magnetic complex micelle sPEG/HA/CSO-SS-Hex/Fe3O4/GA might have potential implications for the chemotherapy of TNBC.

    更新日期:2019-11-01
  • Borneol, a messenger agent, improves central nervous system drug delivery through enhancing blood-brain barrier permeability: a preclinical systematic review and meta-analysis.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-20
    Qun Zheng,Zi-Xian Chen,Meng-Bei Xu,Xiao-Li Zhou,Yue-Yue Huang,Guo-Qing Zheng,Yan Wang

    To achieve sufficient blood-brain barrier (BBB), penetration is one of the biggest challenges in the development of diagnostic and therapeutic for central nervous system (CNS) disorders. Here, we conducted a systematic review and meta-analysis to assess the preclinical evidence and possible mechanisms of borneol for improving co-administration of CNS drug delivery in animal models. The electronic literature search was conducted in six databases. Fifty-eight studies with 63 comparisons involved 1137 animals were included. Among 47 studies reporting the assessments of CNS drug concentration, 45 studies showed the significant effects of borneol for improving CNS drug delivery (p<.05), whereas 2 studies showed no difference (p>.05). Nineteen comparisons showed borneol up-regulated BBB permeability (p<.05) using brain EB content (n = 8), Rh 123 content (n = 4), brain imaging agent content (n = 2), brain water content (n = 1) and observing ultrastructure of BBB (n = 4), whereas three studies showed no difference or unclear results. Seven studies reported the safety, in which one study showed borneol was reversible changes in the BBB penetration; six studies showed borneol did not increase co-administration of blood drugs concentration of peripheral tissues (p > .05). Effects of borneol are closely associated with inhibition of efflux protein function, releasement of tight junction protein, increasement of vasodilatory neurotransmitters, and inhibition of active transport by ion channels. In conclusion, borneol is a promising candidate for CNS drug delivery, mainly through mediating a multi-targeted BBB permeability.

    更新日期:2019-11-01
  • A journey from the endothelium to the tumor tissue: distinct behavior between PEO-PCL micelles and polymersomes nanocarriers.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-13
    Agathe Figarol,Laure Gibot,Muriel Golzio,Barbara Lonetti,Anne-Françoise Mingotaud,Marie-Pierre Rols

    Polymeric nanocarriers must overcome several biological barriers to reach the vicinity of solid tumors and deliver their encapsulated drug. This study assessed the in vitro and in vivo passage through the blood vessel wall to tumors of two well-characterized polymeric nanocarriers: poly(ethyleneglycol-b-ε-caprolactone) micelles and polymersomes charged with a fluorescent membrane dye (DiO: 3,3'-dioctadecyloxacarbo-cyanine perchlorate). The internalization and translocation from endothelial (human primary endothelial cells HUVEC) to cancer cells (human tumor cell line HCT-116) was studied in conventional 2D monolayers, 3D tumor spheroids, or in an endothelium model based on transwell assay. Micelles induced a faster DiO internalization compared to polymersomes but the latter crossed the endothelial monolayer more easily. Both translocation rates were enhanced by the addition of a pro-inflammatory factor or in the presence of tumor cells. These results were confirmed by early in vivo experiments. Overall, this study pointed out the room for the improvement of polymeric nanocarriers design to avoid drug losses when crossing the blood vessel walls.

    更新日期:2019-11-01
  • Dual-modified cationic liposomes loaded with paclitaxel and survivin siRNA for targeted imaging and therapy of cancer stem cells in brain glioma.
    Drug Deliv. (IF 3.829) Pub Date : 2018-10-03
    Xiyang Sun,Ying Chen,Hui Zhao,Guanglei Qiao,Meiyang Liu,Chunlei Zhang,Daxiang Cui,Lijun Ma

    Development of safe, efficient nanocomplex for targeted imaging and therapy of cancer stem cells in brain glioma has become a great challenge. Herein, a low-density lipoprotein receptor-related protein and a RNA aptamer bound CD133 were used as dual-targeting ligands to prepare dual-modified cationic liposomes (DP-CLPs) loaded with survivin siRNA and paclitaxel (DP-CLPs-PTX-siRNA) for actively targeting imaging and treating CD133+ glioma stem cells after passing through the blood-brain barrier. After being administrated with DP-CLPs-PTX-siRNA nanocomplex, DP-CLPs showed a persistent target ability to bind glioma cells and brain microvascular endothelial cells (BCECs) and to deliver drugs (PTX/siRNA) to CD133+ glioma stem cells. Prepared DP-CLPs-PTX-siRNA nanocomplex showed very low cytotoxicity to BCECs, but induced selectively apoptosis of CD133+ glioma stem cells, and improved CD133+ glioma stem cells' differentiation into non-stem-cell lineages, also markedly inhibited tumorigenesis, induced CD133+ glioma cell apoptosis in intracranial glioma tumor-bearing nude mice and improved survival rates. In conclusion, prepared DP-CLPs-PTX-siRNA nanocomplex selectively induced CD133+ glioma stem cell apoptosis in vitro and in vivo exhibits great potential for targeted imaging and therapy of brain glioma stem cells.

    更新日期:2019-11-01
  • Enhanced gene transfection efficiency by low-dose 25 kDa polyethylenimine by the assistance of 1.8 kDa polyethylenimine.
    Drug Deliv. (IF 3.829) Pub Date : 2018-09-23
    Hui Zhang,Zhiyi Chen,Meng Du,Yue Li,Yuhao Chen

    Gene therapy is a promising strategy for treatments of various diseases. Efficient and safe introduction of therapeutic genes into targeted cells is essential to realize functions of the genes. High-molecular-weight polyethylenimines (HMW PEIs) including 25 kDa branched PEI and 22 kDa linear PEI are widely used for in vitro gene transfection. However, high-gene transfection efficiency is usually accompanied with high cytotoxicity, which hampers their further clinical study. On the contrary, low-molecular-weight polyethylenimines (LMW PEIs) such as 1.8 kDa PEI and 800 Da PEI show good biocompatibility but their applications are limited by the poor DNA condensation capability. In this study, we find that 1.8 kDa PEI, but not 800 Da PEI combined with low-dose 25 kDa PEI could significantly promote gene transfection with low cytotoxicity. Plasmids encoding enhanced green fluorescence protein (EGFP) were delivered by the combined PEI and gene transfection efficiency was evaluated by microscopic observation and flow cytometry. Parameters including concentrations of 25 kDa PEI and 1.8 kDa PEI and preparation ways were further optimized. This study presents an efficient and safe combined PEI-based non-viral gene delivery strategy with potential for in vivo applications.

    更新日期:2019-11-01
  • A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo.
    Drug Deliv. (IF 3.829) Pub Date : 2018-09-06
    Youngbum Yoo,Sun-Jung Yoon,So Yeon Kim,Deok-Won Lee,Sewook Um,Hoon Hyun,Sung Ok Hong,Dae Hyeok Yang

    Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin⋅hydrochloride (DOX⋅HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX⋅HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18 hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX⋅HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX⋅HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.

    更新日期:2019-11-01
  • Touch-actuated microneedle array patch for closed-loop transdermal drug delivery.
    Drug Deliv. (IF 3.829) Pub Date : 2018-09-06
    Jingbo Yang,Zhipeng Chen,Rui Ye,Jiyu Li,Yinyan Lin,Jie Gao,Lei Ren,Bin Liu,Lelun Jiang

    To date, only approximately 20 drugs synthesized with small molecules have been approved by the FDA for use in traditional transdermal patches (TTP) owing to the extremely low permeation rate of the skin barrier for macromolecular drugs. A novel touch-actuated microneedle array patch (TMAP) was developed for transdermal delivery of liquid macromolecular drugs. TMAP is a combination of a typical TTP and a solid microneedle array (MA). High doses of liquid drug formulations, especially heat-sensitive compounds can be easily filled and stored in the drug reservoir of TMAPs. TMAP can easily penetrate the skin and automatically retract from it to create microchannels through the stratum corneum (SC) layer using touch-actuated 'press and release' actions for passive permeation of liquid drugs. Comparison of subcutaneous injection, TTP, solid MA, and dissolvable MA, indicated that insulin-loaded TMAP exhibited the best hypoglycemic effect on type 1 diabetic rats. A 'closed-loop' permeation control was also provided for on-demand insulin delivery based on feedback of blood glucose levels (BGLs). Twenty IU-insulin-loaded TMAP maintained the type 1 diabetic rats in a normoglycemic state for approximately 11.63 h, the longest therapeutic duration among all previously reported results on microneedle-based transdermal patches. TMAP possesses excellent transdermal drug delivery capabilities.

    更新日期:2019-11-01
  • Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting.
    Drug Deliv. (IF 3.829) Pub Date : 2018-09-05
    Liuxiang Chu,Aiping Wang,Ling Ni,Xiuju Yan,Yina Song,Mingyu Zhao,Kaoxiang Sun,Hongjie Mu,Sha Liu,Zimei Wu,Chunyan Zhang

    Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

    更新日期:2019-11-01
  • Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer's disease.
    Drug Deliv. (IF 3.829) Pub Date : 2018-08-16
    Shengnuo Fan,Yuqiu Zheng,Xuan Liu,Wenli Fang,Xiaoyu Chen,Wang Liao,Xiuna Jing,Ming Lei,Enxiang Tao,Qiulan Ma,Xingmei Zhang,Rui Guo,Jun Liu

    Alzheimer's disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease.

    更新日期:2019-11-01
  • Intra-articular injection of triamcinolone acetonide releasing biomaterial microspheres inhibits pain and inflammation in an acute arthritis model.
    Drug Deliv. (IF 3.829) Pub Date : 2019-03-08
    Imke Rudnik-Jansen,Karin Schrijver,Nina Woike,Anna Tellegen,Sabine Versteeg,Pieter Emans,George Mihov,Jens Thies,Niels Eijkelkamp,Marianna Tryfonidou,Laura Creemers

    Inflammation of the synovium and joint capsule is a main driver of pain in an osteoarthritic (OA) joint. Triamcinolone acetonide (TAA) is a classical corticosteroid that reduces synovitis and alleviates pain, albeit transiently. Biomaterial-based local TAA release may prolong the suppression of pain without the need for multiple injections. Polylactic-co-glycolic acid (PLGA) formulations of TAA prolong OA pain relief to a limited extent. A novel polyesteramide (PEA) microsphere platform allows for extended release in the OA joint for over 3 months. To evaluate their effect on pain and inflammation, TAA-loaded microspheres were intra-articularly delivered to the knee joint in a rat model of acute arthritis induced by intra-articular injection of streptococcal cell wall peptidoglycan-polysaccharide (PGPS) and subsequent flare-ups by intravenous PGPS injections. PEA-loaded microspheres were benchmarked with TAA-loaded PLGA microspheres and bolus TAA injection. TAA treatments were injected intra-articularly before the first induced flare-up. TAA-loaded PEA and PLGA microspheres reduced joint swelling and signs of pain-like behavior over the entire study period, as assessed by weight bearing and referred mechanical hypersensitivity, whereas bolus suspension was effective for a shorter time period. TAA-loaded PEA microspheres reduced lameness to a greater extent than TAA-loaded PLGA microspheres. In conclusion, a single intra-articular injection of TAA-loaded PEA microspheres reduced joint swelling and induced longer pain relief compared to bolus injection. Hence relief of inflammation and pain by PEA-based delivery of TAA may prove to be effective and durable.

    更新日期:2019-11-01
  • Low-density lipoprotein decorated silica nanoparticles co-delivering sorafenib and doxorubicin for effective treatment of hepatocellular carcinoma.
    Drug Deliv. (IF 3.829) Pub Date : 2019-02-26
    Junfeng Ye,Ruoyan Zhang,Wengang Chai,Xiaohong Du

    Combinational therapy is usually considered as a preferable approach for effective cancer therapy. Especially, combinational chemotherapies targeting different molecular targets are of particular interest due to its high flexibility as well as efficiency. In our study, the surface of silica nanoparticles (SLN) was modified with low-density lipoprotein (LDL) to construct platform (LDL-SLN) capable of specifically targeting low-density lipoprotein receptors (LDLRs) that overexpressing in hepatocellular carcinoma (HCC). In addition, the versatile drug loading capacity of LDL-SLN was employed to fabricate a preferable drug delivery system to co-deliver sorafenib (Sor) and doxorubicin (Dox) for combinational chemotherapy of HCC. Our results revealed that the LDL-SLN/Sor/Dox nanoparticles with size around 100 nm showed preferable stability in physiological environments. Moreover, the LDL-SLN/Sor/Dox could target LDLR overexpressed HepG2 cells. More importantly, both in vitro and in vivo experiments demonstrated that the LDL-SLN/Sor/Dox exerted elevated antitumor efficacy compared to Sor or Dox alone, which indicated that LDL-SLN/Sor/Dox could be a powerful tool for effective combinational chemotherapy of HCC.

    更新日期:2019-11-01
  • Multistage delivery of CDs-DOX/ICG-loaded liposome for highly penetration and effective chemo-photothermal combination therapy.
    Drug Deliv. (IF 3.829) Pub Date : 2018-11-22
    Xiao Xue,Ting Fang,Luyao Yin,Jianqi Jiang,Yunpeng He,Yinghui Dai,Dongkai Wang

    Nanoparticles (NPs) have proven to be effective drug carriers in diagnosis and therapy of cancer. But, they faced a contradictory issue that NPs with large size appear weak tumor penetration, meanwhile small size resulted in poor tumor retention. Herein, we fabricated doxorubicin conjugated carbon dots (CDs-DOX) and indocyanine green (ICG)-loaded liposomes (ICG-LPs) named CDs-ICG-LPs using a modified reverse phase evaporation process, and with high incorporation in the aqueous core. The CDs-ICG-LPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the CDs-ICG-LPs showed higher temperature response, faster DOX release under laser irradiation. In the meantime, the fluorescence of DOX and ICG in CDs-ICG-LPs was also visualized for the process of subcellular location in vitro. In comparison with chemo or photothermal treatment alone, the combined treatment of CDs-ICG-LPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive HepG2 cells. In vivo antitumor activities demonstrated CDs-ICG-LPs could reach higher antitumor activity compared with CDs-DOX and ICG-LPs for H22 tumor cells, and suppressed H22 tumor growth in vivo. Notably, no systemic toxicity occurrence was observed after repeated dose of CDs-ICG-LPs with laser irradiation. Hence, the well-defined CDs-ICG-LPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy.

    更新日期:2019-11-01
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