基于SiO2@PMLA纳米复合物构建粒径可变、序贯释药特性的多级抗肿瘤释药体系

Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. Inadequate drug delivery not only weakens the therapeutic effect, but also causes drug resistance of tumor cells, especially for deep tumor tissue. So，based on variable particle size and drug combination therapy, a multistage nano-drug delivery system with multi-functional properties, including long circulation time, high permeability and cellular uptake, is constructed to realize abundant drug delivery and sequential drug release in the tumor tissue. Inorganic-organic composite nanomaterial is used to synthesize small-size nano-carriers (SN, MSNs@PMLA-iRGD). Curcumin and doxorubicin were encapsulated in SN by adsorption and bonding. Then, SN units are covalently linked via 3- or 4-armed polyethylene glycol (PEG) to form large-size nano-carriers (LN). When the LN reach to the tumor site by the enhanced permeability and retention (EPR) effect, they would be cleaved into SN in the presence of high-expression enzyme, resulting in high tumor penetration and retention. Besides, sequential release of curcumin and doxorubicin is utilized to enhance the chemotherapy effect, thus improving the anticancer activity. In vivo and in vivo experiments would be performed to investigate the effects of size-tunable property and sequential drug release on anti-tumor activity and the inhibition of drug resistance of tumor cells, providing a new multi-mode strategy for designing ideal tumor targeting nano-drug delivery systems of high efficiency.

通常纳米释药体系在肿瘤中的分布并不均匀，不充分的药物递送不仅削弱了治疗效果，还会引起未充分摄取药物的肿瘤细胞（特别是深部肿瘤组织）产生耐药性。本课题从粒径转换、联合给药两个方面构建兼具长循环、高渗透特性的靶向多级纳米释药体系，以期实现纳米载体在肿瘤组织中充分的药物递送及序贯释药。采用无机-有机复合纳米材料组成小粒径纳米载体（SN），姜黄素、阿霉素分别以吸附、键合的方式包载于SN，进而通过3或4-arm PEG共价连接组装成较大粒径释药体系（LN），在肿瘤组织利用酶促断裂反应释放小的纳米载药库SN，研究载体粒径及粒径转换对肿瘤组织渗透、入胞的影响；考察序贯释药协同抗肿瘤作用，评价有效杀死肿瘤细胞（表层及深部）并抑制肿瘤耐药的靶向治疗效果。体内外生物学实验探讨运用粒径转换及序贯释药方式充分杀伤肿瘤细胞的可行性，为构建高效靶向纳米释药体系提供新的多模式设计策略。

通常纳米药物在肿瘤中的分布并不均匀，不充分的药物递送不仅削弱了治疗效果，还会引起未充分摄取药物的肿瘤细胞（特别是深部肿瘤组织）产生耐药性。针对肿瘤纳米载药体系体内应用的瓶颈问题，本课题从构建兼具长循环、高渗透特性的靶向多级纳米释药体系入手，设计了粒径可变的“球棒结构”纳米释药体系及共载药体系，以期实现纳米载体在肿瘤组织中充分的药物递送及协同抗肿瘤作用。首先制备载药小粒径纳米载体介孔硅（MSN），粒径约40nm，通过4-arm PEG共价连接组装成较大粒径的载体MSNs-pp-PEG，粒径约为110nm，进而研究了载体粒径及粒径转换对肿瘤组织渗透、入胞的影响。在正常生理环境下载药体系保持较大粒径，具备体内长循环特性；在肿瘤组织通过酶促反应完成粒径转换，释放小的纳米载药库，以增强对肿瘤组织的渗透扩散，进入肿瘤深部发挥作用。体内抑制肿瘤生长实验和生存曲线均表明，相比于小粒径的MSNs/DOX和固定大粒径的MSNs-PEG/DOX，可发生粒径转换的MSNs-pp-PEG/DOX具有最佳抗肿瘤效果。药物协同作用的研究发现，聚苹果酸共载药体系在给药量低于游离药物时，仍表现出良好的协同抗肿瘤作用，不同化学键的连接可实现两种化疗药物的序贯释放，有望更好的解决单一化疗药物副作用多以及多药耐药等瓶颈问题。课题构建的独特的递药体系可以克服药物载体设计中的“粒径困境”，充分利用不同粒径载体的优势，为构建多重功能粒径转换载体的研究提供了新思路。

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