Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy.
Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy.
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用于神经胶质瘤化疗和放疗的缺氧响应性脂质聚（缺氧放射增敏聚前药）纳米颗粒。
作者：
Hua L;Wang Z;Zhao L;Mao H;Wang G;Zhang K;Liu X;Wu D;Zheng Y;Lu J;Yu R;Liu H
恶性胶质瘤的治疗是肿瘤治疗面临的挑战。除手术和化疗外，放疗（RT）是胶质瘤治疗的最有效方式之一。然而，恶性胶质瘤的RT治疗面临两个关键挑战：首先，胶质瘤由于其瘤内缺氧而对辐射具有抗性;其次，放射增敏剂可能缺乏靶向特异性，这可能导致肿瘤中放射增敏剂浓度较低，并在正常组织中产生毒副作用。因此，设计了新型血管肽-2-脂质-聚-（甲硝唑）n（ALP-（MIs）n）低氧放射增敏剂-聚前药纳米粒（NPs）以增强对胶质瘤的放射增敏作用。研究方法：本研究合成了不同程度和生物降解性的低氧放射增敏剂MIs基聚前药（P-（MIs）n）作为疏水核。将P-（MIs）n与DSPE-PEG 2000、angiopep-2-DSPE-PEG 2000和卵磷脂混合，通过一步纳米沉淀法自组装ALP-（MIs）n。ALP-（MIs）n包裹阿霉素（DOX）（ALP-（MIs）n/DOX）并在用于胶质瘤化疗和放疗的缺氧条件下引发DOX的释放。使用活体动物荧光/生物发光成像在原位胶质瘤中测试体内胶质瘤靶向。在体外和体内研究了ALP-（MIs）n对RT的增敏作用以及ALP-（MIs）n/DOX联合化疗和RT治疗胶质瘤的作用。结果：ALP-（MIs）n/DOX在脑胶质瘤中有效蓄积，全身给药后可到达缺氧脑胶质瘤部位。这些ALP-（MIs）n对胶质瘤表现出显着的放射增敏作用，并实现了化疗和RT联合治疗胶质瘤的体外和体内研究。结论：综上所述，我们构建了一种脂质聚（缺氧放射增敏聚前药）纳米颗粒，用于增强胶质瘤的RT敏感性，实现胶质瘤的放、化疗联合治疗。
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.
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