肿瘤干细胞来源的载药微颗粒抗肿瘤作用及机制研究

Ideal nano drug delivery systems (NDDSs) targeting cancer stem cells (CSCs) should overcome the sequential physiological barriers in vivo and be efficiently internalized by CSCs. We recently found that chemotherapeutic microparticles derived from normal cancer cells (Drug@2D MPs) could be preferentially taken up by CSCs, resulting in excellent antitumor efficacy in clinical trials. Based on the understanding that the biomechanical properties of nanoparticles such as softness has a profound impact on the in vivo processing, we constructed softer chemotherapeutic microparticles derived from CSCs, which were selected by three dimensional soft fibrin gels (Drug@3D MPs). Our preliminary data showed that Drug@3D MPs exhibited stronger anticancer activity than Drug@2D MPs. This project will develop a variety of Drug@3D MPs by encapsulating different anticancer drugs and assess their universal enhanced anticancer activities in multiple tumor models. The in vivo processing of Drug@3D MPs including long circulation, tumor accumulation and penetration, and cellular uptake by CSCs will be systematically investigated. The effects of the softness of Drug@MPs on their in vivo processing, cytotoxicity against CSCs and anticancer effects will be evaluated. This project will provide an insight into developing softness-tailorable NDDSs, and also the basis of novel chemotherapeutic MPs for targeting CSCs.

理想的靶向肿瘤干细胞的纳米药物需克服体内系列生理屏障并被肿瘤干细胞有效摄取。我们前期参与的一项研究发现普通肿瘤细胞来源的载药微颗粒能选择性杀死肿瘤干细胞，临床研究呈现优良的抗肿瘤效果。基于对“纳米载药系统生物力学特性如软硬度深刻影响纳米药物体内过程”的认识，我们利用软三维纤维蛋白胶分选技术，制备了更柔软的肿瘤干细胞来源的载药微颗粒，初步药效学实验表明其抗肿瘤效果更强。本项目在此基础上，将对肿瘤干细胞来源的微颗粒负载不同抗癌药物，在多种肿瘤模型上验证其增强抗肿瘤效果的普适性；通过比较研究不同软硬度载药微颗粒的长循环、肿瘤富集、肿瘤组织渗透以及被肿瘤干细胞摄取等特性，揭示载药微颗粒的软硬度对其体内过程和抗肿瘤作用影响及机制。上述研究将为软硬度可调的新型纳米载药系统构建提供新思路，并为发展一类新型高效的靶向肿瘤干细胞载药微颗粒提供依据。

胞外囊泡由于具有稳定性好、生物相容性高、细胞靶向性等特点，在用作抗肿瘤药物递送载体方面已引起关注。本项目构建从三维软纤维蛋白胶筛选的肿瘤干细胞（CSCs）来源微颗粒用作抗肿瘤药物递送载体，由于其具有独特的柔软性，相比培养在普通细胞培养盘中的肿瘤细胞来源微颗粒，更能有效促进在肿瘤组织富集、穿越血管进入肿瘤深部、及被CSCs有效摄取，且发现骨架蛋白cytospin-A在调控CSCs来源微颗粒柔软性方面发挥重要作用。该研究阐明CSCs来源微颗粒的力学特性调控抗肿瘤药物的递送效率，为发展高效的抗肿瘤药物递送载体提供新思路。在此基础上进一步发展其他基于胞外囊泡的抗肿瘤纳米药物递送载体，如肿瘤细胞外排的外泌体包裹多孔硅纳米药物、负载Bi2Se3纳米点和阿霉素的肿瘤细胞来源微颗粒载药系统，用于改善肿瘤治疗效果及实现肿瘤诊疗一体化。本项目对提高抗肿瘤药物治疗效果提供理论依据。