兼具肿瘤靶向富集及胞内快速释药的pH敏感高分子前药纳米输送体系的构建

pH sensitive prodrug nano-delivery systems have been paid tremendous attention in recent years, because of their recognition to the mildly acidic environment at tumor tissue and accurate controlling drug release. However, their clinical applications are limited by the physiological barriers at tumor site and intracellular drug release efficiency. Therefore, it is urgent to develop a special pH-sensitive polymeric prodrug with tumoral targeting accumulation and intracellular rapid drug release to enhance chemotherapeutic efficacy. In this project, a series of pH-sensitive polymeric prodrug delivery systems are prepared by utilizing pH-sensitive orthoester bond, chemotherapy drugs such as paclitaxel (PTX) and 10-hydroxycamptothecine (HCPT), and functional ligands such as methoxy polyethylene glycol (MPEG) and fluoride, based on the existence of evident pH gradient at tumor tissue, therefore achieving (i) remaining stable in the blood circulation and enhancing cellular uptake via PEGylation/dePEGylation and fluorination; (ii) responding to tumoral extracellular pH (6.5-7.0) following dynamic size change for promoting tumor targeting accumulation by means of main-chain poly(orthoester); (iii) efficient drug release from side-chain orthoester-based prodrug for enhancing cell-killing ability by rapid response to tumoral intracellular pH (4.0-6.0). This research will provide theoretical and practical foundation for the design and preparation of safely and efficiently polymeric prodrug delivery systems.

pH敏感前药纳米输送体系由于能识别肿瘤微酸环境且精确调控药物释放行为，近些年来在抗肿瘤领域倍受关注。目前如何克服肿瘤部位的生理屏障，提高该材料体系的靶向富集以及胞内快速释药能力直接决定了其临床应用前景。本项目拟根据肿瘤组织pH的梯度分布，设计以酸敏感键原酸酯为连接键，紫杉醇和10-羟基喜树碱为模型药物，聚乙二醇单甲醚（MPEG）、氟化物为功能配体，制备多功能的pH敏感高分子前药纳米输送体系。以期实现：（i）通过PEG化/去PEG化及氟化作用提高血液循环稳定性及癌细胞的摄取能力；（ii）通过主链聚原酸酯响应肿瘤胞外pH（6.5-7.0），引起粒径的动态变化，增强肿瘤靶向富集能力；（iii）通过侧链原酸酯键键合化疗药物，快速响应胞内pH（4.0-6.0），引发原药高效释放，增强杀死肿瘤细胞的能力。通过本项目的研究，将为设计和制备安全、高效的高分子前药输送体系提供理论与实践基础。

pH敏感纳米药物由于能识别肿瘤微酸环境且精确调控药物释放行为，近些年来在抗肿瘤领域倍受关注。目前如何克服肿瘤部位的生理屏障，提高该材料体系的靶向富集以及胞内快速释药能力直接决定了其临床应用前景。本研究首先通过优化原酸酯键周围亲疏水环境（如控制聚乙烯醇的原酸酯接枝率、原酸酯直接键合聚乙二醇），成功构建了特异性响应肿瘤胞外微酸环境的纳米药物，通过引发粒径的动态变化以及可拆卸的PEG化作用增强肿瘤靶向富集、渗透、摄取以及快速释药能力；再进一步引入维生素E聚乙二醇1000琥珀酸酯(TPGS)、吲哚美辛、维生素B6、维生素E、肉桂醛和色胺等功能配体，成功制备pH敏感靶向纳米前药，在显著增强肿瘤富集、摄取的同时，显著提高胞内药物释放，逆转耐药和癌细胞杀灭能力；最后整合前两类纳米药物的优势成功构建了兼具肿瘤靶向富集及胞内快速释放的pH敏感高分子前药纳米输送体系，具有精准的结构、高药物负载率、长期储存和循环稳定性、高效逆转多药耐药以及协同杀死肿瘤细胞的能力，在明显降低药物毒副作用的同时，显著增强抗肿瘤疗效。本研究的设计思路在国内外文献中未见有类似的研究报道，属原始性创新，可为设计及制备安全、高效的肿瘤靶向高分子前药传输系统提供理论与实践基础，具有重要的基础研究价值和临床应用前景。