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Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy
Theranostics ( IF 12.4 ) Pub Date : 2018-10-06 , DOI: 10.7150/thno.26225
Lei Hua , Zhen Wang , Liang Zhao , Honglin Mao , Guanghui Wang , Kairuo Zhang , Xuejiao Liu , Dongmei Wu , Yuanlin Zheng , Jun Lu , Rutong Yu , Hongmei Liu

Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas.

Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo.

Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo.

Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.

Keywords: glioma, radiosensitized polyprodrug, chemo- and radiotherapy, hypoxia-responsive, blood-brain barrier



中文翻译:

缺氧反应性脂质聚(缺氧放射增敏多药前体)纳米颗粒用于神经胶质瘤的化学和放射治疗

恶性神经胶质瘤的治疗是癌症治疗面临的挑战。除手术和化学疗法外,放射疗法(RT)是神经胶质瘤治疗的最有效方式之一。然而,RT面临恶性神经胶质瘤治疗面临两个关键挑战:首先,已知神经胶质瘤由于其肿瘤内缺氧而对放射线有抵抗力;第二,放射增敏剂可能缺乏靶标特异性,这可能导致放射增敏剂在肿瘤中的浓度降低,并在正常组织中产生毒副作用。因此,设计了新型的血管肽-2-脂质-聚(甲硝唑)n(ALP-(MIs)n)缺氧放射增敏剂-多药前体纳米颗粒(NPs)以增强对神经胶质瘤的放射增敏作用。

方法:本研究合成了不同程度的低氧放射增敏剂MIs基多前药(P-(MIs)n)作为疏水核。将P-(MIs)n与DSPE-PEG2000,angiopep-2-DSPE-PEG2000和卵磷脂混合,通过一步纳米沉淀法自组装ALP-(MIs)n。ALP-(MIs)n封装了阿霉素(DOX)(ALP-(MIs)n / DOX),并在低氧条件下激发DOX的释放,以用于神经胶质瘤的化学疗法和放射疗法。使用活体动物荧光/生物发光成像在原位神经胶质瘤中测试了体内神经胶质瘤的靶向性。还在体内体外研究了ALP-(MIs)n对RT敏化的敏感性以及化学疗法和ALP-(MIs)n / DOX RT联合治疗胶质瘤的效果

结果:系统性体内给药后 ALP-(MIs)n / DOX有效积聚在神经胶质瘤中,并可能到达缺氧性神经胶质瘤部位。这些ALP-(MIS)N表现出对神经胶质瘤两个神经胶质瘤治疗显著放射增敏作用,并实现了联合化疗和RT体外体内

结论:总之,我们构建了脂质-聚(缺氧放射增敏的多药前体)纳米颗粒,以增强神经胶质瘤的RT敏感性,并实现放射疗法和化学疗法联合治疗神经胶质瘤。

关键词:神经胶质瘤,放射增敏前药,化学和放射疗法,缺氧反应性,血脑屏障

更新日期:2018-10-08
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