还原敏感可逆交联生物可降解聚合物囊泡用于蛋白质药物的肿瘤靶向释放

In this project, we set to design reduction-sensitive reversibly crosslinked biodegradable chimaeric polymersomes for highly efficient loading and delivery of therapeutic proteins for tumor-targeted protein delivery. The tumor-targeting chimaeric biodegradable polymersomes are made of two asymmetric triblock copolymers: poly(ethylene glycol)-disulfide containing polyester-poly(acrylic acid) (PEG-SSPE-PAA) and ligand-decorated PEG-SSPE-PAA (ligand-PEG-SSPE-PAA). Herewith, the PEG as outer shell has nonfouling property and supports long circulation. The tumor specific targeting moieties cRGD or AS-1411 on the polymersome surfaces can afford highly efficient tumor cell uptake of polymersomal drugs. The inner shell PAA designed to be shorter than PEG facilitates efficient encapsulation of therapeutic proteins via electrostatic interaction or hydrogen bonding. The hydrophobic polymersomal membrane cores not only present as physical barrier protecting proteins from degradation during circulation, but also are able to prevent the dissociation of the polymersomes by reversibly crosslinking via the pendent disulfide bonds. Once the protein loaded polymersomes are introduced into the body, they will circulate until reaching the target cancer cells. Through the receptor-ligand interaction mediated endocytosis the polymersomal drugs can be efficiently internalized by these tumor cells. Inside cytosol, the polymersomes will be de-crosslinked due to the GSH triggered disulfide cleavage. The subsequent swelling of the polymersomes, owing to the generation of two thiol groups and the low Tg of the polymers, results in fast protein release intracellularly. The fast release might inhibit the multidrug resistance leading to highly efficient cancer therapy. Therefore, these reduction sensitive reversibly crosslinked biodegradable chimaeric polymersomes are highly promising for efficient tumor-targeted protein delivery. In addition, hydrophobic anticancer drugs (e.g. paclitaxel and doxorubicin) can be co-loaded into the membrane of the polymersomes, potentially useful for combination cancer therapy.

本项目将研制主动靶向肿瘤、还原敏感可逆交联、具有不对称膜结构的生物可降解聚合物囊泡用于蛋白质药物的高效肿瘤靶向释放。该囊泡由聚乙二醇-含双硫五元环功能化生物可降解聚合物-聚丙烯酸嵌段聚合物（PEG-SSPE-PAA）和靶向分子修饰的PEG-SSPE-PAA（Ligand-PEG-SSPE-PAA）自组装后交联得到。囊泡外表面PEG保证长循环；偶联的靶向分子cRGD或AS-1411可促进囊泡的高效、特异性的肿瘤细胞内吞；囊泡内PAA（比PEG短）可实现蛋白质的高效包裹；壁膜上的双硫五元环功能基团在DTT催化下形成线性聚双硫得到还原敏感可逆交联稳定的囊泡；被肿瘤细胞内吞后，囊泡在细胞内还原环境下自动解交联，药物快速释放，产生高抗癌活性，可望实现对黑色素瘤、乳腺癌、前列腺癌等恶性肿瘤的安全高效靶向治疗。此外，该囊泡可同时高效运载蛋白质和疏水抗癌药，有望实现肿瘤尤其是具耐药性肿瘤的协同靶向治疗。

蛋白质等亲水药物的临床应用由于循环时间短、生物利用度低而受到限制。用纳米载体装载时存在装载效率低、循环不稳定易发生药物早释、进靶细胞药物浓度低易于导致耐药性、药效差、毒副作用大和/或不可降解等问题。为解决纳米载体在体内的不稳定和最终的生物降解性问题，我们设计了具有自主知识产权的含双硫五元环的1，2-二硫戊环三亚甲基碳酸酯（DTC）、通过开环聚合ROP制备了DTC的均聚以及和其他环酯和环碳酸酯的共聚物，以此制备了一系列完全生物可降解、生物相容性优异、还原敏感可逆交联、循环稳定却在肿瘤细胞内可应激释放药物的聚合物胶束和囊泡纳米药物系统，我们设计了多种表面偶联肿瘤特异性靶向分子的囊泡纳米药物用于亲水药如蛋白质、siRNA和水溶性小分子抗癌药的高效装载和肿瘤靶向治疗。我们主要研究了基于DTC技术的单体制备和聚合物研究及初步探索基于DTC的纳米药物、聚合物囊泡装载阿霉素、具有不对称膜结构的聚合物囊泡装载蛋白质药物、聚合物囊泡装载siRNA和其他水溶性药物、CT增强的聚合物囊泡装载水溶性药物用于肿瘤的诊疗等，在小鼠人皮下和原位肺癌、人原位脑胶质瘤、人原位肝癌、人黑色素瘤、人卵巢癌、及多发性骨髓瘤等的靶向治疗作用，为纳米药物的临床推进和转化奠定了基础。已顺利完成并超过了预定的研究目标：本项目支持下已发表论文26篇,多篇改稿中；申请中国专利21项、国际专利5项；中国授权专利11项，国际授权专利3项。其中有8项专利转让。培养硕士研究生5人，博士研究生3人，博士后出站1人。

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