Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composite Materials, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, College of Materials Science and Engineering, State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-Inorganic Composite Materials, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, College of Materials Science and Engineering, State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
Biomaterials. 2022 Jan;280:121305. doi: 10.1016/j.biomaterials.2021.121305. Epub 2021 Dec 2.
Metastasis has been widely recognized as the most lethal threats for cancer patients. Due to their special genetic and environmental context, cancer stem cells (CSCs) which are resistant to most cytotoxic drugs and radiation, are considered as the dominant culprit for metastasis. Thus, the efficient targeting and thorough elimination of CSCs are significantly urgent for the enhancement of therapeutic efficacy. Herein, we developed a facile and smart photothermal-chemo therapeutic nano-assembly system, of which the surface was modified by a sheddable PEG shell and acid-activatable pro-penetration peptide, to surmount the physiological barriers in targeting CSCs. A highly-efficient diradical-featured croconium-based photothermal agent and a natural cytotoxic heat shock protein (HSP) inhibitor were co-loaded in redox-sensitive chitosan matrices to realize the synergistic photothermal-chemo therapy. Within solid tumors, the PEG shell that prevents the nano-assembly from mononuclear phagocytic clearance could rapidly leave to expose the positively charged chitosan, and the detached iRGD could further actuate the tumor penetration of chitosan nanoparticles, and allow the CSCs targeting by selective recognition of CD44 protein. Owing to the HSP inhibition and chemo-sensitization, both the CSCs and non-CSCs could be thoroughly eliminated by the designed nano-assembly, largely inhibiting the tumor growth and metastasis. This work provides a potential strategy for CSCs-targeting drug delivery to solve the CSCs-related metastasis.
转移已被广泛认为是癌症患者最致命的威胁。由于其特殊的遗传和环境背景，对大多数细胞毒性药物和辐射具有抗性的癌症干细胞（CSCs）被认为是转移的主要罪魁祸首。因此，有效地靶向和彻底消除 CSCs 对于提高治疗效果至关重要。在此，我们开发了一种简便且智能的光热化疗纳米组装系统，其表面被可脱落的聚乙二醇（PEG）壳和酸激活的穿透肽修饰，以克服靶向 CSCs 时的生理屏障。高效双自由基特征的克罗酮基光热剂和天然细胞毒性热休克蛋白（HSP）抑制剂被共装载在氧化还原敏感的壳聚糖基质中，以实现协同光热化疗。在实体瘤中，防止纳米组装被单核吞噬细胞清除的 PEG 壳会迅速离开，暴露出带正电荷的壳聚糖，而分离的 iRGD 则可以进一步激活壳聚糖纳米颗粒的肿瘤穿透，并通过对 CD44 蛋白的选择性识别实现对 CSCs 的靶向。由于 HSP 抑制和化疗增敏作用，设计的纳米组装可以彻底消除 CSCs 和非 CSCs，从而大大抑制肿瘤生长和转移。这项工作为 CSCs 靶向药物递送提供了一种潜在的策略，以解决与 CSCs 相关的转移问题。
