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  • Polymer nitric oxide donors potentiate the treatment of experimental solid tumours by increasing drug accumulation in the tumour tissue
    J. Control. Release (IF 7.786) Pub Date : 2017-11-16
    M. Studenovsky, L. Sivak, O. Sedlacek, R. Konefal, V. Horkova, T. Etrych, M. Kovar, B. Rihova, M. Sirova

    The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.

    更新日期:2017-11-17
  • Microneedle arrays coated with charge reversal pH-sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses
    J. Control. Release (IF 7.786) Pub Date : 2017-11-15
    Huu Thuy Trang Duong, Nak Won Kim, Thavasyappan Thambi, V.H. Giang Phan, Min Sang Lee, Yue Yin, Ji Hoon Jeong, Doo Sung Lee

    Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4+ and CD8+ T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b-poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH 4.03) and becoming negative charge when exposed to physiological pH conditions (pH 7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery.

    更新日期:2017-11-17
  • Cardiac progenitor cells activated by mitochondrial delivery of resveratrol enhance the survival of a doxorubicin-induced cardiomyopathy mouse model via the mitochondrial activation of a damaged myocardium
    J. Control. Release (IF 7.786) Pub Date : 2017-11-14
    Jiro Abe, Yuma Yamada, Takeda Atsuhito, Hideyoshi Harashima

    It has been reported that transplanting native cells would lack efficiency without producing artificial cell-tissue, due to the exaggerated oxidative stress in doxorubicin-induced cardiomyopathy. We attempted to activate cardiac progenitor cells (CPCs) by delivering resveratrol to mitochondria using a mitochondrial drug delivery system (MITO-Porter system). We first evaluated the viability of H9c2 cells (a cardio myoblast cell line) after doxorubicin treatment, where H9c2 cells were co-cultured with or without the mitochondria activated CPCs (referred to herein as MITO cell). We next evaluated the survival rate of doxorubicin treated mice, with or without the injection of MITO cells into the myocardium. Finally, we examined the molecular mechanism of the cell therapy by detecting oxidative stress and the induction of apoptosis in addition to quantification of the mRNA and protein levels about oxidative phosphorylation (OXPHOS). The MITO cell transplanted mice lived significantly longer than the conventional CPC transplanted ones. Oxidative stress and massive cell death were both significantly reduced in the MITO cell transplanted hearts, in which the expression levels of OXPHOS protein and gene were also higher than the control group. In doxorubicin-induced cardiomyopathy, the transplantation of MITO cells, which possess activated mitochondria, is more efficient compared to conventional CPC transplantation.

    更新日期:2017-11-15
  • Acid-activatable oxidative stress-inducing polysaccharide nanoparticles for anticancer therapy
    J. Control. Release (IF 7.786) Pub Date : 2017-11-14
    Wooyoung Yoo, Donghyuck Yoo, Eunmi Hong, Eunkyeong Jung, Yebin Go, Berwin Singh, Gilson Khang, Dongwon Lee

    Drug delivery systems have been extensively developed to enhance the therapeutic efficacy of drugs by altering their pharmacokinetics and biodistribution. However, the use of high quantities of drug delivery systems can cause toxicity due to their poor metabolism and elimination. In this study, we developed polysaccharide-based drug delivery systems which exert potent therapeutic effects and could display synergistic therapeutic effects with drug payloads, leading to dose reduction. Cinnamaldehyde, a major component of cinnamon is known to induce anticancer activity by generating ROS (reactive oxygen species). We developed cinnamaldehyde-conjugated maltodextrin (CMD) as a polymeric prodrug of cinnamaldehyde and a drug carrier. Cinnamaldehyde was conjugated to the hydroxyl groups of maltodextrin via acid-cleavable acetal linkages, allowing facile formulation of nanoparticles and drug encapsulation. CMD nanoparticles induced acid-triggered ROS generation to induce apoptotic cell death. Camptothecin (CPT) was used as a model drug to investigate the potential of CMD nanoparticles as a drug carrier and also evaluate the synergistic anticancer effects with CMD nanoparticles. CPT-loaded CMD nanoparticles exhibited significantly higher anticancer activity than empty CMD nanoparticles and CPT alone in the study of mouse xenograft models, demonstrating the synergistic therapeutic effects of CMD with CPT. Taken together, we believe that CMD nanoparticles hold tremendous potential as a polymeric prodrug of cinnamaldehyde and a drug carrier in anticancer therapy.

    更新日期:2017-11-15
  • Current progress and challenges of nanoparticle-based therapeutics in pain management
    J. Control. Release (IF 7.786) Pub Date : 2017-11-13
    Vanesa Andreu, Manuel Arruebo

    Pain is a widespread and growing health problem worldwide that exerts a considerable social and economic impact on both patients and healthcare systems and, therefore, on society in general. Although current treatment modalities include a wide variety of pharmacological and non-pharmacological approaches, due to the complexity of pain and individual differences in clinical response these options are not always effective in mitigating and relieving pain. In addition, some pain drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics and opioids show several unfavorable side effects. Therefore, current research advances in this medical field are based on the development of potential treatments to address many of the unmet needs and to overcome the existing limitations in pain management. Nanoparticle drug delivery systems present an exciting opportunity as alternative platforms to improve efficacy and safety of medications currently in use. Herein, we review a broad range of nanoparticle formulations (organic nanostructures and inorganic nanoparticles), which have been developed to encapsulate an array of painkillers, paying special attention to the key advantages that these systems offer, (compared to the use of the free drug), as well as to the more relevant results of preclinical studies in animal models. Additionally, we will briefly discuss the impact of some of these nanoformulations in clinical trials.

    更新日期:2017-11-14
  • Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity
    J. Control. Release (IF 7.786) Pub Date : 2017-11-13
    Eric M. Mastria, Leon Y. Cai, Matthew J. Kan, Xinghai Li, Jeffrey L. Schaal, Steven Fiering, Michael D. Gunn, Mark W. Dewhirst, Smita K. Nair, Ashutosh Chilkoti

    Strategies that enhance the host antitumor immune response promise to revolutionize cancer therapy. Optimally mobilizing the immune system will likely require a multi-pronged approach to overcome the resistance developed by tumors to therapy. Recently, it has become recognized that doxorubicin can contribute to re-establishing host antitumor immunity through the generation of immunogenic cell death. However, the potential for delivery strategies to further enhance the immunological effects of doxorubicin has not been adequately examined. We report herein that Chimeric Polypeptide Doxorubicin (CP-Dox), a nanoparticle formulation of doxorubicin, enhances antitumor immunity. Compared to free doxorubicin, a single intravenous (IV) administration of CP-Dox at the maximum tolerated dose increases the infiltration of leukocytes into the tumor, slowing tumor growth and preventing metastasis in poorly immunogenic 4T1 mammary carcinoma. We demonstrate that the full efficacy of CP-Dox is dependent on CD8 + T cells and IFN-γ. CP-dox treatment also repolarized intratumoral myeloid cells towards an antitumor phenotype. These findings demonstrate that a nanoparticle drug is distinct from the free drug in its ability to productively stimulate antitumor immunity. Our study strongly argues for the use of antitumor immunotherapies combined with nanoparticle-packaged chemotherapy.

    更新日期:2017-11-14
  • Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells
    J. Control. Release (IF 7.786) Pub Date : 2017-11-13
    Freya Joris, Lynn De Backer, Thijs Van de Vyver, Chiara Bastiancich, Stefaan C. De Smedt, Koen Raemdonck

    Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.

    更新日期:2017-11-14
  • Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets
    J. Control. Release (IF 7.786) Pub Date : 2017-11-13
    Muzna Sadia, Basel Arafat, Waqar Ahmed, Robert E. Forbes, Mohamed A. Alhnan

    Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has considerable potential for patient-specific dosage form. However, the use of FDM 3D printing in tablet manufacturing requires large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforating channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0 mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface are/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width ≥ 0.6 mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6 mm) were more efficient at accelerating drug release than longer channels (18.2 mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from rich polymeric structures.

    更新日期:2017-11-14
  • Extending antigen release from particulate vaccines results in enhanced antitumor immune response
    J. Control. Release (IF 7.786) Pub Date : 2017-11-13
    Chintan H. Kapadia, Shaomin Tian, Jillian L. Perry, David Sailer, J. Christopher Luft, Joseph M. DeSimone

    Tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) play a critical role in an anti-tumor immune response. However, vaccination intended to elicit a potent CD8+ T cell responses employing tumor-associated peptide antigens, are typically ineffective due to poor immunogenicity. Previously, we engineered a polyethylene glycol (PEG) hydrogel-based subunit vaccine for the delivery of an antigenic peptide and CpG (adjuvant) to elicit potent CTLs. In this study, we further examined the effect of antigen release kinetics on their induced immune responses. A CD8+ T cell epitope peptide from OVA (CSIINFEKL) and CpG were co-conjugated to nanoparticles utilizing either a disulfide or a thioether linkage. Subsequent studies comparing peptide release rates as a function of linker, determined that the thioether linkage provided sustained release of peptide over 72 h. Ability to control the release of peptide resulted in both higher and prolonged antigen presentation when compared to disulfide-linked peptide. Both NP vaccine formulations resulted in activation and maturation of bone marrow derived dendritic cells (BMDCs) and induced potent CD8+ T cell responses when compared to soluble antigen and soluble CpG. Immunization with either disulfide or thioether linked vaccine constructs effectively inhibited EG7-OVA tumor growth in mice, however only treatment with the thioether linked vaccine construct resulted in enhanced survival.

    更新日期:2017-11-14
  • Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease
    J. Control. Release (IF 7.786) Pub Date : 2017-11-11
    Atsushi Tamura, Nobuhiko Yui

    Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl β-cyclodextrin (HP-β-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile β-CD-based polyrotaxanes (PRXs) comprising multiple β-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of β-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded β-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-β-CD. In this study, the therapeutic effect of the PRXs in a mouse model of NPC disease was investigated. Weekly administration of the PRXs significantly prolonged the life span and suppressed neurodegeneration in mice, even at a dose of 500 mg/kg, a markedly lower dose than previously reported for HP-β-CD. Detailed analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild-type mice. Acid-labile PRX is therefore a promising candidate for potentiating the efficacy of β-CD in the treatment of NPC disease.

    更新日期:2017-11-13
  • Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles
    J. Control. Release (IF 7.786) Pub Date : 2017-11-11
    Tianyang Ren, Qian Wang, Ying Xu, Lin Cong, Jingxin Gou, Xiaoguang Tao, Yu Zhang, Haibing He, Tian Yin, Haotian Zhang, Yan Zhang, Xing Tang

    Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2 ± 5.7 nm, zeta potential of + 40.90 ± 3.05 mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.

    更新日期:2017-11-11
  • Towards topical microRNA-directed therapy for epidermal disorders
    J. Control. Release (IF 7.786) Pub Date : 2017-11-10
    Kehinde Ross

    There remains an unmet need dermatological need for innovative topical agents that achieve better long term outcomes with fewer side effects. Modulation of the expression and activity of microRNA (miRNAs) represents an emerging translational framework for the development of such innovative therapies because changes in the expression of one miRNA can have wide-ranging effects on diverse cellular processes associated with disease. In this short review, the roles of miRNA in epidermal development, psoriasis, cutaneous squamous cell carcinoma and re-epithelisation are highlighted. Consideration is given to the delivery of oligonucleotides that mimic or inhibit miRNA function using vehicles such as cell penetrating peptides, spherical nucleic acids, deformable liposomes and liquid crystalline nanodispersions. Formulation of miRNA-directed oligonucleotides with such skin-penetrating epidermal agents will drive the development of RNA-based cutaneous therapeutics for deployment as primary or adjuvant therapies for epidermal disorders.

    更新日期:2017-11-11
  • Transport mechanism of lipid covered saquinavir pure drug nanoparticles in intestinal epithelium
    J. Control. Release (IF 7.786) Pub Date : 2017-11-10
    Dengning Xia, Yuan He, Qiuxia Li, Cunde Hu, Wei Huang, Yunhai Zhang, Feng Wan, Chi Wang, Yong Gan

    Pure drug nanoparticles (NPs) represent a promising formulation for improved drug solubility and controlled dissolution velocity. However, limited absorption by the intestinal epithelium remains challenge to their clinical application, and little is known about how these NPs within the cells are transported. To improve cellular uptake and transport of pure nanodrug in cells, here, a lipid covered saquinavir (SQV) pure drug NP (Lipo@nanodrug) was designed by modifying a pure SQV NP (nanodrug) with a phospholipid bilayer. We studied their endocytosis, intracellular trafficking mechanism using Caco-2 cell model. Uptake of Lipo@nanodrug by Caco-2 cells was 1.91-fold greater than that of pure nanodrug via processes involving cell lipid raft. The transcellular transport of Lipo@nanodrug across Caco-2 monolayers was 3.75-fold and 1.92-fold higher than that of coarse crystals and pure nanodrug, respectively. Within cells, Lipo@nanodrug was mainly localized in the endoplasmic reticulum and Golgi apparatus, leading to transcytosis of Lipo@nanodrug across intestinal epithelial cells, whereas pure nanodrug tended to be retained and to dissolve in cell and removed by P-gp–mediated efflux. In rats, the oral bioavailability of the model drug SQV after Lipo@nanodrug administration was 4.29-fold and 1.77-fold greater than after coarse crystal and pure nanodrug administration, respectively. In conclusion, addition of a phospholipid bilayer to pure drug NP increased their cellular uptake and altered their intracellular processing, helping to improve drug transport across intestinal epithelium. To our knowledge, this is the first presentation of the novel phospholipid bilayer covered SQV pure drug NP design, and a mechanistic study on intracellular trafficking in in vitro cell models has been described. The findings provide a new platform for oral delivery of poorly water-soluble drugs.

    更新日期:2017-11-10
  • Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid
    J. Control. Release (IF 7.786) Pub Date : 2017-11-10
    E. Péraudeau, L. Cronier, A. Monvoisin, P. Poinot, C. Mergault, F. Guilhot, I. Tranoy-Opalinski, B. Renoux, S. Papot, J. Clarhaut

    Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates. In this study, we demonstrate in vitro that a combination of dexamethasone (Dexa) and valproic acid (VPA) increases FRα expression selectively at the surface of FR-overexpressing cancer cells. The same stimulation was observed in vivo in KB-tumor xenografts when mice are treated with this combined treatment. This effect is reversible since treatment interruption induces the return of FR expression at basal level. When incubated with Dexa and VPA, the β-galactosidase-responsive folate-monomethyl auristatin E (MMAE) conjugate, called MGAF, exhibits higher cytotoxic activity on several FR-positive human cancer cell lines, compared to its administration as a single agent. This improved toxicity results from the enhanced concentration of MMAE released within cancer cells after internalization and subsequent enzymatic activation of MGAF. Higher deposition of MMAE is also observed in vivo after up-regulation of FR expression level in tumor xenografts, induced by the prior administration of the Dexa/VPA combination. In this model, MGAF/Dexa/VPA combined therapy results in an 81% inhibition of tumor growth compared to the control group, while MGAF used in monotherapy is inefficient. Since Dexa and VPA are currently used in humans, this finding could be of great interest for further development of folate-drug conjugates, in particular for those that are presently under clinical investigation.

    更新日期:2017-11-10
  • Overcoming antibiotic resistance: Is siderophore Trojan horse conjugation an answer to evolving resistance in microbial pathogens?
    J. Control. Release (IF 7.786) Pub Date : 2017-11-10
    Kalyani Dhusia, Archana Bajpai, P.W. Ramteke

    Comparative study of siderophore biosynthesis pathway in pathogens provides potential targets for antibiotics and host drug delivery as a part of computationally feasible microbial therapy. Iron acquisition using siderophore models is an essential and well established model in all microorganisms and microbial infections a known to cause great havoc to both plant and animal. Rapid development of antibiotic resistance in bacterial as well as fungal pathogens has drawn us at a verge where one has to get rid of the traditional way of obstructing pathogen using single or multiple antibiotic/chemical inhibitors or drugs. ‘Trojan horse’ strategy is an answer to this imperative call where antibiotic are by far sneaked into the pathogenic cell via the siderophore receptors at cell and outer membrane. This antibiotic once gets inside, generates a ‘black hole’ scenario within the opportunistic pathogens via iron scarcity. For pathogens whose siderophore are not compatible to smuggle drug due to their complex conformation and stiff valence bonds, there is another approach. By means of the siderophore biosynthesis pathways, potential targets for inhibition of these siderophores in pathogenic bacteria could be achieved and thus control pathogenic virulence. Method to design artificial exogenous siderophores for pathogens that would compete and succeed the battle of intake is also covered with this review. These manipulated siderophore would enter pathogenic cell like any other siderophore but will not disperse iron due to which iron inadequacy and hence pathogens control be accomplished. The aim of this review is to offer strategies to overcome the microbial infections/pathogens using siderophore.

    更新日期:2017-11-10
  • Drug delivery systems functionalized with bone mineral seeking agents for bone targeted therapeutics
    J. Control. Release (IF 7.786) Pub Date : 2017-11-08
    S.G. Rotman, D.W. Grijpma, R.G. Richards, T.F. Moriarty, D. Eglin, O. Guillaume

    The systemic administration of drugs to treat bone diseases is often associated with poor uptake of the drug in the targeted tissue, potential systemic toxicity and suboptimal efficacy. In order to overcome these limitations, many micro- and nano-sized drug carriers have been developed for the treatment of bone pathologies that exhibit specific affinity for bone. Drug carriers can be functionalized with bone mineral seekers (BMS), creating a targeted drug delivery system (DDS) which is able to bind to bone and release therapeutics directly at the site of interest. This class of advanced DDS is of tremendous interest due to their strong affinity to bone, with great expectation to treat life-threatening bone disorders such as osteomyelitis, osteosarcoma or even osteoporosis. In this review, we first explain the mechanisms behind the affinity of several well-known BMS to bone, and then we present several effective approaches allowing the incorporation BMS into advanced DDS. Finally, we report the therapeutic applications of BMS based DDS under development or already established. Understanding the mechanisms behind the biological activity of recently developed BMS and their integration into advanced therapeutic delivery systems are essential prerequisites for further development of bone-targeting therapies with optimal efficacy.

    更新日期:2017-11-10
  • Leakage kinetics of the liposomal chemotherapeutic agent Doxil: The role of dissolution, protonation, and passive transport, and implications for mechanism of action
    J. Control. Release (IF 7.786) Pub Date : 2017-11-07
    Luisa M. Russell, Margot Hultz, Peter C. Searson

    Doxil, a liposomal formulation of the chemotherapeutic drug doxorubicin, is FDA-approved for multiple indications. Doxil liposomes are designed to retain doxorubicin in circulation, minimize clearance by the mononuclear phagocyte system, and limit uptake in healthy tissue. Although pharmacokinetic data and survival statistics from clinical trials provide insight into distribution and efficacy, many details of the mechanism of action remain unresolved, despite the importance in translating liposome-based drug delivery systems to other molecules and cargo. Therefore, the objective of this study is to quantitatively assess the kinetics of doxorubicin leakage from Doxil liposomes. In contrast to previous studies, we consider three processes: dissolution of solid doxorubicin, protonation/deprotonation of soluble doxorubicin, and passive transport of neutral doxorubicin across the lipid bilayer of the liposomes. Experiments were performed for Doxil, Doxil-like liposomes, and Doxil-like liposomes with reduced cholesterol and pegylation. To mimic physiological conditions, we also performed experiments in serum and under slightly acidic conditions at pH 5. We show that crystalline doxorubicin dissolution can be described by a first order rate constant of 1.0 × 10− 9 cm s− 1 at 37 °C. Doxorubicin leakage can be described by first order rate constant for transport across the lipid bilayer with values in the range from 1 to 3 × 10− 12 cm s− 1 at 37 °C. Based on these results we discuss implications for the mechanism of action, taking Doxil pharmacokinetics into account.

    更新日期:2017-11-10
  • Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent
    J. Control. Release (IF 7.786) Pub Date : 2017-11-07
    Jean Kim, Max Kudisch, Nina Rosa Konichi da Silva, Hiroyuki Asada, Eri Aya-Shibuya, Michele M. Bloomer, Sri Mudumba, Robert B. Bhisitkul, Tejal A. Desai

    Long-term treatment of glaucoma, a major leading cause of blindness, is challenging due to poor patient compliance. Therefore, a drug delivery device that can achieve drug release over several months can be highly beneficial for glaucoma management. Here, we evaluate the long-term pharmacokinetics and therapeutic efficacy of polycaprolactone intracameral drug delivery devices in rabbit eyes. Our study showed that a single drug delivery device loaded with a proprietary hypotensive agent, DE-117, reduced intraocular pressure in normotensive rabbits significantly for 23 weeks. In addition, we demonstrated that concentration of DE-117 and its hydrolyzed active form (hDE-117) was maintained in the aqueous humor and the target tissue (iris-ciliary body) up to 24 weeks. Our proof-of-concept glaucoma implant shows potential as a long-term treatment that circumvents patient compliance barriers compared to current treatment via eye drops.

    更新日期:2017-11-10
  • Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging
    J. Control. Release (IF 7.786) Pub Date : 2017-11-06
    Andreas I. Jensen, Gregory W. Severin, Anders E. Hansen, Frederikke P. Fliedner, Rasmus Eliasen, Ladan Parhamifar, Andreas Kjær, Thomas L. Andresen, Jonas R. Henriksen

    Liposomes are nanoparticles used in drug delivery that distribute over several days in humans and larger animals. Radiolabeling with long-lived positron emission tomography (PET) radionuclides, such as manganese-52 (52Mn, T½ = 5.6 days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with 52Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 (64Cu, T½ = 12.7 h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal chelates is widely debated but studies that mimic a realistic in vivo setting are lacking. Therefore, we employed these four radiolabeled liposome types as platforms to demonstrate a new concept for such in vivo evaluation, here of the chelates 52Mn-DOTA and 64Cu-DOTA. This was done by comparing “shielded” remote-loaded with “exposed” surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90 min at 55 °C) and surface labeling (55 °C for 2 h) of 52Mn gave excellent radiolabeling efficiencies of 97–100% and 98–100% respectively, and the liposome biodistribution was imaged by PET for up to 8 days. Liposomes with surface-conjugated 52Mn-DOTA exhibited a significantly shorter plasma half-life (T½ = 14.4 h) when compared to the remote-loaded counterpart (T½ = 21.3 h), whereas surface-conjugated 64Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2 ± 2.9 h versus 20.3 ± 1.2 h). From our data, we conclude the successful remote-loading of liposomes with 52Mn, and furthermore that 52Mn-DOTA may be unstable in vivo whereas 64Cu-DOTA appears suitable for quantitative imaging.

    更新日期:2017-11-10
  • Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs
    J. Control. Release (IF 7.786) Pub Date : 2017-11-05
    Mark Davis

    Poorly water-soluble drugs are a significant and ongoing issue for the pharmaceutical industry. An overview of recent developments for the preparation of spray-dried delivery systems is presented. Examples include amorphous solid dispersions, spray dried dispersions, microparticles, nanoparticles, surfactant systems and self-emulsifying drug delivery systems. Several aspects of formulation are considered, such as pre-screening, choosing excipient(s), the effect of polymer structure on performance, formulation optimisation, ternary dispersions, fixed-dose combinations, solvent selection and component miscibility. Process optimisation techniques including nozzle selection are discussed. Comparisons are drawn with other preparation techniques such as hot melt extrusion, freeze drying, milling, electro spinning and film casting. Novel analytical and dissolution techniques for the characterization of amorphous solid dispersions are included. Progress in understanding of amorphous supersaturation or recrystallisation from solution gathered from mechanistic studies is discussed. Aspects of powder flow and compression are considered in a section on downstream processing. Overall, spray drying has a bright future due to its versatility, efficiency and the driving force of poorly soluble drugs.

    更新日期:2017-11-10
  • 更新日期:2017-11-05
  • Transcription factors: Time to deliver
    J. Control. Release (IF 7.786) Pub Date : 2017-11-04
    Alexey V. Ulasov, Andrey A. Rosenkranz, Alexander S. Sobolev
    更新日期:2017-11-05
  • Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase
    J. Control. Release (IF 7.786) Pub Date : 2017-11-03
    Ilaria Basile, Afitz Da Silva, Khaled El Cheikh, Anastasia Godefroy, Morgane Daurat, Alice Harmois, Marc Perez, Catherine Caillaud, Henry-Vincent Charbonné, Bernard Pau, Magali Gary-Bobo, Alain Morère, Marcel Garcia, Marie Maynadier
    更新日期:2017-11-05
  • 更新日期:2017-11-01
  • Mapping of drug distribution in the rabbit liver tumor model by complementary fluorescence and mass spectrometry imaging
    J. Control. Release (IF 7.786) Pub Date : 2017-10-31
    Katrin Fuchs, Andras Kiss, Pierre E. Bize, Rafael Duran, Alban Denys, Gérard Hopfgartner, Gerrit Borchard, Olivier Jordan
    更新日期:2017-11-01
  • Doxorubicin-conjugated Escherichia coli Nissle 1917 swimmers to achieve tumor targeting and responsive drug release
    J. Control. Release (IF 7.786) Pub Date : 2017-10-31
    Songzhi Xie, Long Zhao, Xiaojie Song, Maosheng Tang, Chuanfei Mo, Xiaohong Li
    更新日期:2017-11-01
  • Mapping the pharmaceutical design space by amorphous ionic liquid strategies
    J. Control. Release (IF 7.786) Pub Date : 2017-10-31
    Johannes Wiest, Marco Saedtler, Anja Balk, Benjamin Merget, Toni Widmer, Heike Bruhn, Marc Raccuglia, Elbast Walid, Franck Picard, Helga Stopper, Wolfgang Dekant, Tessa Lühmann, Christoph Sotriffer, Bruno Galli, Ulrike Holzgrabe, Lorenz Meinel
    更新日期:2017-11-01
  • Systematic approaches for biodiagnostics using exhaled air
    J. Control. Release (IF 7.786) Pub Date : 2017-10-27
    Pravin Shende, Jai Vaidya, Yogesh A. Kulkarni, R.S. Gaud
    更新日期:2017-10-28
  • Small molecule delivery to solid tumors with chitosan-coated PLGA particles: A lesson learned from comparative imaging
    J. Control. Release (IF 7.786) Pub Date : 2017-10-27
    Jinho Park, Yihua Pei, Hyesun Hyun, Mark A. Castanares, David S. Collins, Yoon Yeo
    更新日期:2017-10-27
  • Cyclodextrins as versatile building blocks for regenerative medicine
    J. Control. Release (IF 7.786) Pub Date : 2017-10-26
    Carmen Alvarez-Lorenzo, Carlos A. García-González, Angel Concheiro
    更新日期:2017-10-27
  • Adaptation of vectors and drug-inducible systems for controlled expression of transgenes in the tumor microenvironment
    J. Control. Release (IF 7.786) Pub Date : 2017-10-24
    Joanna Poutou, Maria Bunuales, Manuela Gonzalez-Aparicio, Beatriz German, Ines Zugasti, Ruben Hernandez-Alcoceba
    更新日期:2017-10-24
  • Using siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation in psoriasis
    J. Control. Release (IF 7.786) Pub Date : 2017-10-23
    Houshang Nemati, Mohammad-Hosein Ghahramani, Reza Faridi-Majidi, Babak Izadi, Gholamreza Bahrami, Seyed-Hamid Madani, Gholamreza Tavoosidana
    更新日期:2017-10-24
  • Rational designing of an antidote nanoparticle decorated with abiotic polymer ligands for capturing and neutralizing target toxins
    J. Control. Release (IF 7.786) Pub Date : 2017-10-20
    Hiroyuki Koide, Hiroki Tsuchida, Masahiko Nakamoto, Anna Okishima, Saki Ariizumi, Chiaki Kiyokawa, Tomohiro Asai, Yu Hoshino, Naoto Oku
    更新日期:2017-10-20
  • Multifunctional nanoparticles co-delivering EZH2 siRNA and etoposide for synergistic therapy of orthotopic non-small-cell lung tumor
    J. Control. Release (IF 7.786) Pub Date : 2017-10-20
    Zhi-qiang Yuan, Wei-liang Chen, Ben-gang You, Yang Liu, Shu-di Yang, Ji-zhao Li, Wen-jing Zhu, Xiao-feng Zhou, Chun Liu, Xue-nong Zhang
    更新日期:2017-10-20
  • Injectable hydrogels for ophthalmic applications
    J. Control. Release (IF 7.786) Pub Date : 2017-10-20
    Kai Wang, Zongchao Han
    更新日期:2017-10-20
  • 更新日期:2017-10-20
  • 更新日期:2017-10-20
  • Long-lived tissue resident HIV-1 specific memory CD8 + T cells are generated by skin immunisation with live virus vectored microneedle arrays
    J. Control. Release (IF 7.786) Pub Date : 2017-10-19
    Marija Zaric, Pablo Daniel Becker, Catherine Hervouet, Petya Kalcheva, Barbara Ibarzo Yus, Clement Cocita, Lauren Alexandra O'Neill, Sung-Yun Kwon, Linda Sylvia Klavinskis
    更新日期:2017-10-20
  • From concept to in vivo testing: Microcontainers for oral drug delivery
    J. Control. Release (IF 7.786) Pub Date : 2017-10-18
    Chiara Mazzoni, Fabio Tentor, Sophie Strindberg Andersen, Line Hagner Nielsen, Stephan Sylvest Keller, Tommy Sonne Alstrøm, Carsten Gundlach, Anette Müllertz, Paolo Marizza, Anja Boisen
    更新日期:2017-10-18
  • Exosome is a mechanism of intercellular drug transfer: Application of quantitative pharmacology
    J. Control. Release (IF 7.786) Pub Date : 2017-10-18
    Jin Wang, Bertrand Z. Yeung, Minjian Cui, Cody J. Peer, Ze Lu, William D. Figg, M. Guillaume Wientjes, Sukyung Woo, Jessie L.-S. Au
    更新日期:2017-10-18
  • Simultaneously overcome tumor vascular endothelium and extracellular matrix barriers via a non-destructive size-controlled nanomedicine
    J. Control. Release (IF 7.786) Pub Date : 2017-10-18
    Binghua Wang, Yongxia Zhai, Jinjin Shi, Luyang Zhuang, Wei Liu, Huijuan Zhang, Hongling Zhang, Zhenzhong Zhang
    更新日期:2017-10-18
  • Accessibility of axonal G protein coupled mu-opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation
    J. Control. Release (IF 7.786) Pub Date : 2017-10-17
    Shaaban A. Mousa, Mohammed Shaqura, Mohammed Al-Madol, Sascha Tafelski, Baled I. Khalefa, Mehdi Shakibaei, Michael Schäfer
    更新日期:2017-10-17
  • Ragweed pollen as an oral vaccine delivery system: Mechanistic insights
    J. Control. Release (IF 7.786) Pub Date : 2017-10-17
    Md Jasim Uddin, Harvinder Singh Gill
    更新日期:2017-10-17
  • Precise laser poration to control drug delivery into and through human nail
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Simon Vanstone, Sarah F. Cordery, James M. Stone, Sergey N. Gordeev, Richard H. Guy
    更新日期:2017-10-17
  • New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Cristian Turato, Anna Balasso, Vinicio Carloni, Claudio Tiribelli, Francesca Mastrotto, Antonio Mazzocca, Patrizia Pontisso
    更新日期:2017-10-17
  • Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Tong-Fei Li, Ke Li, Chao Wang, Xin Liu, Yu Wen, Yong-Hong Xu, Quan Zhang, Qiu-Ya Zhao, Ming Shao, Yan-Ze Li, Min Han, Naoki Komatsu, Li Zhao, Xiao Chen
    更新日期:2017-10-17
  • Multimodal imaging approach to examine biodistribution kinetics of Cabotegravir (GSK1265744) long acting parenteral formulation in rat
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Beat M. Jucker, Hasan Alsaid, Mary Rambo, Stephen C. Lenhard, Bao Hoang, Fang Xie, M. Reid Groseclose, Stephen Castellino, Valeriu Damian, Gary Bowers, Manish Gupta
    更新日期:2017-10-16
  • Bone-targeting nanoparticle to co-deliver decitabine and arsenic trioxide for effective therapy of myelodysplastic syndrome with low systemic toxicity
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Xiaoyan Wu, Zhenhua Hu, Sara Nizzero, Guodong Zhang, R. Maricela Ramirez, Ce Shi, Jin Zhou, Mauro Ferrari, Haifa Shen
    更新日期:2017-10-16
  • Photochemical delivery of bleomycin induces T-cell activation of importance for curative effect and systemic anti-tumor immunity
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Ole-Jacob Norum, Ane Sofie Viset Fremstedal, Anette Weyergang, Jakub Golab, Kristian Berg
    更新日期:2017-10-16
  • Defining optimal permeant characteristics for ultrasound-mediated gastrointestinal delivery
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Carl M. Schoellhammer, Yiyun Chen, Cody Cleveland, Daniel Minahan, Taylor Bensel, June Y. Park, Sarah Saxton, Young-Ah Lucy Lee, Lucas Booth, Robert Lange, Giovanni Traverso
    更新日期:2017-10-16
  • Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy
    J. Control. Release (IF 7.786) Pub Date : 2017-10-16
    Cetin Tas, Jessica C. Joyce, Hiep X. Nguyen, Padmanabhan Eangoor, Jennifer S. Knaack, Ajay K. Banga, Mark R. Prausnitz
    更新日期:2017-10-16
  • Novel bilayer dissolving microneedle arrays with concentrated PLGA nano-microparticles for targeted intradermal delivery: Proof of concept
    J. Control. Release (IF 7.786) Pub Date : 2017-10-14
    Lalit K. Vora, Ryan F. Donnelly, Eneko Larraneta, Patricia González-Vázquez, Raghu Raj Singh Thakur, Pradeep R. Vavia
    更新日期:2017-10-14
  • An intelligent re-shieldable targeting system for enhanced tumor accumulation
    J. Control. Release (IF 7.786) Pub Date : 2017-10-13
    Zhenpeng Hu, Jinlong Ma, Fei Fu, Chen Cui, Xiaomin Li, Xinyu Wang, Wei Wang, Yeda Wan, Zhi Yuan
    更新日期:2017-10-13
  • 3D printed multi-compartment capsular devices for two-pulse oral drug delivery
    J. Control. Release (IF 7.786) Pub Date : 2017-10-13
    A. Maroni, A. Melocchi, F. Parietti, A. Foppoli, L. Zema, A. Gazzaniga
    更新日期:2017-10-13
  • Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment
    J. Control. Release (IF 7.786) Pub Date : 2017-10-13
    Shweta Sharma, Aman P. Mann, Tarmo Mölder, Venkata Ramana Kotamraju, Robert Mattrey, Tambet Teesalu, Erkki Ruoslahti
    更新日期:2017-10-13
  • Transfer-molded wrappable microneedle meshes for perivascular drug delivery
    J. Control. Release (IF 7.786) Pub Date : 2017-10-13
    JiYong Lee, Dae Hyun Kim, Kang Ju Lee, Il Ho Seo, Seung Hyun Park, Eui Hwa Jang, Youngjoo Park, Young-Nam Youn, WonHyoung Ryu
    更新日期:2017-10-13
  • 更新日期:2017-10-12
  • Thermoresponsive β-glucan-based polymers for bimodal immunoradiotherapy – Are they able to promote the immune system?
    J. Control. Release (IF 7.786) Pub Date : 2017-10-12
    Lenka Loukotová, Jan Kučka, Mariia Rabyk, Anita Höcherl, Kristýna Venclíková, Olga Janoušková, Petr Páral, Věra Kolářová, Tomáš Heizer, Luděk Šefc, Petr Štěpánek, Martin Hrubý
    更新日期:2017-10-12
  • PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells
    J. Control. Release (IF 7.786) Pub Date : 2017-10-07
    Jong-Sung Park, Yumin Oh, Ogyi Park, Catherine A. Foss, Sung Mook Lim, Dong-Gyu Jo, Dong Hee Na, Martin G. Pomper, Kang Choon Lee, Seulki Lee
    更新日期:2017-10-08
  • Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing
    J. Control. Release (IF 7.786) Pub Date : 2017-10-06
    Natalja Genina, Johan Peter Boetker, Stefano Colombo, Necati Harmankaya, Jukka Rantanen, Adam Bohr
    更新日期:2017-10-07
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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