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。

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.