智能靶向多功能磷脂-聚合物杂化纳米粒克服MDR及用于肿瘤化疗-光热诊疗的研究

The aim of this project is to develop temperature/redox responsive multifunctional lipid-polymer hybrid nanopartices (LPNPs) using self-assembly strategy to achieve various functions including tumor targeting, specific intracellular delivery, programmed release of gene/drug, combined cancer imaging and chemo-photothermal therapy. The LPNPs can incorporate chemotherapeutic drug (doxorubicin, DOX) and photothermal agent (indocyanine green, ICG) in the redox-responsive hydrophobic polymeric core, and absorb negatively charged MDR1 siRNA on the temperature-responsive cationic lipid layer. In addition, the PEG-lipid layer of the LPNPs are modified by FA and molecular modified aTAT peptide to improve tumor targeting and enhance tumor-specific intracellular delivering efficiency. The LPNPs can effectivly accumulate in tumor tissues through EPR passive targeting and FA active targeting, where the modified aTAT would be deshielded in the acidic tumor microenvironment and reactivate TAT's function. In the tumor cells, the LPNPs would escape from the endosome into the cytoplasm and release MDR1 siRNA from the lipid layer firstly, resulting in down-regulation of MDR1 mRNA levels and P-gp expression. Then the release of chemotherapeutics from the polymeric core would be triggered in response to high GSH in the tumor cell, thus leading to effectively kill cancer cells and overcome multidrug resistance. In the meatime, the LPNPs enable NIR fluorescence imaging to in situ monitor the chemothetapeutic effect, and can realize targeting cancer imaging and chemo-photothermal therapy.

本项目通过分子自组装构建一类集肿瘤靶向、高效特异性入胞、可程序释放基因/药物、并实现化疗联合光热疗法及诊疗一体化的温度/还原敏感性多功能磷脂-聚合物杂化纳米粒（LPNPs）。LPNPs在还原敏感聚合物内核中同时包载抗肿瘤药物DOX及近红外荧光分子ICG、在温度敏感磷脂壳层连接沉默多药耐药基因MDR1的siRNA，在磷脂壳层PEG端连接叶酸和分子修饰穿膜肽aTAT。LPNPs通过EPR被动靶向和叶酸主动靶向至肿瘤局部后，aTAT对肿瘤pHe敏锐响应快速去屏蔽为TAT而实现特异性高效穿膜入胞。在肿瘤细胞内LPNPs从内涵体逃逸后，先释放磷脂壳层的MDR1 siRNA而抑制MDR1基因和P-gp表达，然后GSH触发还原敏感内核快速释放DOX并避免被P-gp泵出而克服MDR。在化疗的同时通过ICG近红外荧光成像进行诊断，并基于诊断结果加以激光照射，实现恶性肿瘤的化疗-光热疗法协同治疗及诊疗一体化。

传统的化学疗法面临一些严峻的问题，例如毒副作用大，易产生多药耐药性，缺乏体内药物监测和预后不良。多功能纳米载药系统可以实现多种药物的联合给药，从而实现癌症的联合治疗和诊断。本项目通过分子自组装构建一类集肿瘤靶向、程序化释药、并可实现化疗-光热联合疗法、免疫治疗及诊疗一体化的还原敏感性多功能磷脂-聚合物杂化纳米粒。杂化纳米粒共载化疗药和MDR逆转剂Tariquidar并靶向递送至肿瘤细胞，经GSH触发还原敏感键快速释药实现杀伤肿瘤及克服MDR；通过ICG近红外荧光成像实现杂化纳米粒在体内分布的可视化以达到诊断目的，并基于诊断结果加以808 nm激光照射，实现肿瘤的化疗联合光热治疗；通过靶向共传递抗原和佐剂提高肿瘤微环境中DCs摄取，有效诱导DCs成熟、向淋巴结迁移并呈递抗原，活化T细胞、产生高效的抗肿瘤免疫应答实现肿瘤的免疫治疗。具体研究成果如下：.1.成功地合成了还原敏感性的两亲性共聚物PCL-ss-PEG-ss-PCL，通过分子自组装制备出靶向共载化疗药与MDR逆转剂Tariquidar的磷脂-聚合物杂化纳米粒，其可有效提高纳米粒的肿瘤靶向性，增加耐药细胞对化疗药的摄取，从而克服肿瘤的多药耐药性、增强化疗药的杀伤率。.2.成功构建了可用于肿瘤化疗联合光热治疗并可近红外荧光成像示踪的磷脂-聚合物杂化纳米粒，其具有靶向功能、pH/还原双重响应性、良好的稳定性、载药能力以及较强的光热转换效率，可通过激光促进细胞对纳米粒的摄取和药物释放，其介导的化疗联合光热治疗具有良好的抗肿瘤效果并可示踪药物在动物体内的分布，达到诊疗一体化的目的。.3.成功制备了靶向共传递抗原和佐剂的磷脂-聚合物杂化纳米粒用于肿瘤的免疫治疗。其具有良好的DCs靶向性，促进了DCs表面成熟标志及细胞因子的表达。在预防性和治疗性动物实验模型中，该靶向纳米粒能够刺激机体产生更强的抗肿瘤免疫应答，具有更好的抑制肿瘤生长的效果，并能维持长期高效的肿瘤免疫记忆，可用于肿瘤的免疫治疗。.本项目的研究成果将为多功能纳米药物载体克服肿瘤的多药耐药性、实现体内药物监测、降低毒副作用、实现恶性肿瘤的靶向联合治疗及诊断一体化提供研究基础，同时在学术上为分子自组装磷脂-聚合物杂化纳米粒作为新型药物载体的研发提供思路。

内容获取失败，请点击重试