Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China.
Mol Pharm. 2020 Apr 6;17(4):1028-1048. doi: 10.1021/acs.molpharmaceut.0c00014. Epub 2020 Mar 16.
Currently, clinically used antitumor nanomedicine is usually insufficient to eradicate malignancies, due to the tumor stroma exerting therapeutic resistance and physical barriers for proper drug delivery. As the most abundant cells in the tumor stroma, cancer-associated fibroblasts (CAFs) produce a critical tumor-promoting effect and barriers preventing the physical delivery of nanomedicines through secreting pro-tumorigenic cytokines, increasing solid tumor pressure and interstitial fluid pressure (IFP), and nonspecific internalization. Therefore, beyond treatment centered on cancer cells, researchers are focusing on targeting CAFs to fight stromal-rich tumors. In recent years, a series of novel nano delivery systems have been developed based on specific CAF-targeted ligands and advanced biofunctional materials. On the one hand, CAF-targeted nano delivery systems inhibit the pro-tumor signaling pathway between CAFs and cancer cells to reverse tumorigenesis, immunosuppression, or drug resistance in the tumor microenvironment, thus improving the sensitivity to antitumor treatments. On the other hand, nanostrategies acting on CAFs profoundly contribute to increasing the deep penetration of antitumor drugs through the decrease of solid pressure, IFP, and dense extracellular matrix generation related to the resistance to intratumoral diffusion. In this review, we first introduce the biological mechanisms of CAFs that interfere with nanotherapy. The state-of-the-art passive and active strategies of nano delivery systems targeting CAFs are then summarized, focusing on the therapeutic mechanism involved and the rational design of nano delivery systems. Additionally, the challenges of CAF-targeted nanotherapy are discussed from the perspectives of developing efficient nano delivery systems and potential clinical use.
目前，临床应用的抗肿瘤纳米药物通常不足以根除恶性肿瘤，这是由于肿瘤基质会产生治疗抵抗，并对药物的适当传递构成物理障碍。成纤维细胞是肿瘤基质中最丰富的细胞，通过分泌促肿瘤细胞因子、增加实体瘤压力和间质液压力（IFP）以及非特异性内化，产生关键的促肿瘤效应和物理传递纳米药物的屏障。因此，研究人员除了以癌细胞为中心的治疗方法外，还将重点放在针对 CAF 以对抗富含基质的肿瘤上。近年来，一系列基于特定 CAF 靶向配体和先进的生物功能材料的新型纳米递药系统已经被开发出来。一方面，CAF 靶向纳米递药系统通过抑制 CAFs 与癌细胞之间的促肿瘤信号通路，逆转肿瘤微环境中的肿瘤发生、免疫抑制或耐药性，从而提高抗肿瘤治疗的敏感性。另一方面，作用于 CAFs 的纳米策略通过降低实体瘤压力、IFP 和与肿瘤内扩散阻力相关的致密细胞外基质生成，极大地促进了抗肿瘤药物的深度渗透。在这篇综述中，我们首先介绍了 CAFs 干扰纳米治疗的生物学机制。然后总结了靶向 CAFs 的被动和主动纳米递药系统的最新进展，重点介绍了所涉及的治疗机制和纳米递药系统的合理设计。此外，还从开发高效纳米递药系统和潜在临床应用的角度讨论了 CAF 靶向纳米治疗的挑战。
