Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Methods Mol Biol. 2024;2777:191-204. doi: 10.1007/978-1-0716-3730-2_14.
Nanoparticle drug delivery has been promoted as an effective mode of delivering antineoplastic therapeutics. However, most nanoparticle designs fail to consider the multifaceted tumor microenvironment (TME) that produce pro-tumoral niches, which are often resistant to chemo- and targeted therapies. In order to target the chemoresistant cancer stem-like cells (CSCs) and their supportive TME, in this chapter we describe a nanoparticle-based targeted co-delivery that addresses the paracrine interactions between CSC and non-cancerous mesenchymal stem cells (MSCs) in the TME. Carcinoma-activated MSCs have been shown to increase the chemoresistance and metastasis of CSC. Yet their contributions to protect the CSC TME have not yet been systematically investigated in the design of nanoparticles for drug delivery. Therefore, we describe the fabrication of degradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (120-200 nm), generated with an electrospraying process that encapsulates both a conventional chemotherapeutic, paclitaxel, and a targeted tyrosine kinase inhibitor, sunitinib, to limit MSC interactions with CSC. In the 3D hetero-spheroid model that comprises both CSCs and MSCs, the delivery of sunitinib as a free drug disrupted the MSC-protected CSC stemness and migration. Therefore, this chapter describes the co-delivery of paclitaxel and sunitinib via PLGA nanoparticles as a potential targeted therapy strategy for targeting CSCs. Overall, nanoparticles can provide an effective delivery platform for targeting CSCs and their TME together. Forthcoming studies can corroborate similar combined therapies with nanoparticles to improve the killing of CSC and chemoresistant cancer cells, thereby improving treatment efficiency.
纳米药物输送已被推广为输送抗肿瘤治疗剂的有效方式。然而，大多数纳米颗粒设计都没有考虑到多方面的肿瘤微环境 (TME)，而这些环境会产生促进肿瘤的小生境，这些小生境通常对化疗和靶向治疗有抵抗力。为了靶向化疗耐药的癌症干细胞样细胞 (CSC) 及其支持性肿瘤微环境，在本章中，我们描述了一种基于纳米颗粒的靶向共递药系统，该系统解决了 CSC 与肿瘤微环境中非癌细胞间充质干细胞 (MSC) 之间的旁分泌相互作用。已证明癌激活的 MSC 会增加 CSC 的化疗耐药性和转移。然而，在用于药物输送的纳米颗粒设计中，尚未系统地研究它们对保护 CSC 肿瘤微环境的贡献。因此，我们描述了可降解聚 (乳酸-共-乙醇酸) (PLGA) 纳米颗粒（120-200nm）的制备，该纳米颗粒是通过电喷雾过程产生的，该过程封装了常规化疗药物紫杉醇和靶向酪氨酸激酶抑制剂舒尼替尼，以限制 MSC 与 CSC 的相互作用。在由 CSC 和 MSC 组成的 3D 异质球体模型中，舒尼替尼作为游离药物的递送破坏了 MSC 保护的 CSC 干性和迁移。因此，本章描述了通过 PLGA 纳米颗粒共递紫杉醇和舒尼替尼作为靶向 CSC 的潜在靶向治疗策略。总体而言，纳米颗粒可为靶向 CSC 及其肿瘤微环境提供有效的递药平台。未来的研究可以用纳米颗粒来佐证类似的联合疗法，以提高对 CSC 和化疗耐药癌细胞的杀伤作用，从而提高治疗效率。
