PtIV交联剂制备的siRNA纳米胶囊用于克服肿瘤的多药耐药

Co-delivery of chemotherapeutic agents and siRNA by nanocarriers to overcome the multidrug resistance (MDR) of cancer has recently attracted many attentions. However, conventional co-delivery nancarriers not only need complex fabrication methods, but also would not achieve precisely control of drug release, greatly limiting the efficacy of overcoming the MDR. This project designs to fabricate siPgp nanocapsules using Pt(IV) cross-linker BaPt for overcoming the MDR of A549/DDP drug-resistant lung cancer. Cross-linker BaPt will be synthesized to prepare nanocapsules BaPt-nsiPgp followed by characterization of physical and chemical properties, drug loading capacity and siPgp protection of BaPt-nsiPgp. Next, this project proposes to verify the simultaneous release of two drugs, study the cellular uptake into drug-resistant cancer cells, measure the efficacy of down-regulating P-gp protein and test the cell cytotoxicity of BaPt-nsiPgp. After determination of optimal nanocapsule, its in vivo anticancer afficacy will be tested. Therefore, this project not only is an innovative attempt for solving basic scientific problems, but also holds potential practical applications in overcoming the MDR of cancer and improving the anticancer efficacy.

利用纳米载体共载化疗药和siRNA从而克服肿瘤的多药耐药（MDR）已成为近年来的研究热点。然而常规的共载纳米载体不仅制备方法复杂，且无法实现对药物的精确控制释放，这很大程度上限制了其克服多药耐药的效果。本项目设计利用Pt(IV)交联剂BaPt制备siPgp纳米胶囊BaPt-nsiPgp以克服A549/DDP耐药肺癌的MDR。本项目拟合成交联剂BaPt进而制备纳米胶囊BaPt-nsiPgp，表征其理化性质，载药能力及保护siPgp活性的能力。接着拟继续验证体外两种药物的同时释放性能，研究纳米胶囊的耐药肿瘤细胞摄取，下调P-gp蛋白表达效率及细胞毒性研究。在确定了最佳纳米胶囊之后最后验证其活体抗肿瘤效果。因此，本项研究不仅是一次很有创新性的解决基础科学问题的尝试，同时对于克服肿瘤MDR提高抗肿瘤效果也具有潜在的实际应用价值。

利用纳米载体共载化疗药和siRNA从而克服肿瘤的多药耐药（MDR）已成为近年来的研究热点。然而常规的共载纳米载体不仅制备方法复杂，且无法实现对药物的精确控制释放，这很大程度上限制了其克服多药耐药的效果。本项目设计利用Pt(IV)交联剂BaPt制备siPgp纳米胶囊BaPt-nsiPgp以克服A549/DDP耐药肺癌的MDR。目前已成功合成Pt(IV)交联剂及正电单体Asp，并成功制备共载纳米胶囊BaPt-nSiPgp。之后又进一步验证了纳米胶囊被MCF-7耐铂药肿瘤细胞高效摄取，且能够显著提高杀伤耐药细胞效果。因此，本项目的关键设想已被验证，这表明该课题可以继续实施，可以实现项目预期目标。后续申请人将设计利用肿瘤细胞膜包裹共载纳米胶囊从而屏蔽其表面正电降低毒性，同时肿瘤细胞膜包裹的纳米载体也可以增强稳定性并实现肿瘤细胞的同源靶向，最终实现更强的抗肿瘤作用。该项目拟通过非常简单的一步制备方法构建具有完全创新性的铂药和siRNA共载纳米系统，进而用于克服肿瘤的耐药性。这不仅是一次非常有价值的基础性探索研究和方法学创新，更为抗肿瘤纳米药物载体在解决肿瘤治疗临床问题和实现转化应用方面提供了更多新的机会。