Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
ACS Appl Bio Mater. 2021 Apr 19;4(4):3670-3685. doi: 10.1021/acsabm.1c00141. Epub 2021 Apr 6.
Cancer stem-like cells (CSCs) have emerged as an important target for breast cancer therapy owing to their self-renewability, proliferation, and elevated chemoresistance properties. Here, we present a strategy of eliminating CSCs by differentiation therapy where "forced differentiation" reprograms CSCs so that they lose their intrinsic properties and become susceptible for conventional chemotherapeutic drugs. In this study, we report that a conventional chemotherapeutic paclitaxel enhances the stemness of CSCs, while a phytochemical forskolin being essentially nontoxic to CSCs possesses the intrinsic ability to reprogram them. To achieve simultaneous targeting of CSCs and bulk tumor cells, we used a co-delivery system where liquid crystal nanoparticles (LCN) were co-encapsulated with both paclitaxel and forskolin. LCN showed higher uptake, retention, and penetration potential in CSCs overcoming their high drug efflux property. Moreover, LCN improved the pharmacokinetic parameters of forskolin, which otherwise had very low retention and bioavailability. Forskolin-loaded LCN forced CSCs to exit from their mesenchymal state, which reduced their stemness and chemosensitized them while inhibiting E-cadherin-mediated survival and tumor-initiating potential as well as reversing paclitaxel-induced stemness. We further showed that upon administration of paclitaxel and forskolin co-loaded LCN to an orthotropic xenograft mouse model, the nanomedicine showed enhanced passive tumor targeting capability with very potent antitumor activity that eradicated small solid tumor in a single dose and showed no sign of tumor relapse or systemic toxicity over a long period. Overall, these findings give a proof of concept that co-delivery of forskolin and paclitaxel in a single nanoformulation can achieve overall tumor targeting where forskolin can efficiently reprogram/differentiate CSCs and paclitaxel can induce cytotoxicity in both differentiated CSCs and bulk tumor cells simultaneously. Hence, this study can provide a nanoformulation that can offer an efficient strategy for cancer therapy.
癌症干细胞（CSC）由于其自我更新、增殖和提高的化疗耐药性而成为乳腺癌治疗的一个重要靶点。在这里，我们提出了一种通过分化治疗消除 CSC 的策略，其中“强制分化”重新编程 CSC，使它们失去内在特性并对常规化疗药物敏感。在这项研究中，我们报告说，常规化疗药物紫杉醇增强了 CSC 的干性，而植物化学药物福司可林对 CSC 基本无毒，具有内在的重新编程它们的能力。为了同时靶向 CSC 和肿瘤细胞，我们使用了一种共递药系统，其中液晶纳米粒子（LCN）同时包封紫杉醇和福司可林。LCN 在 CSC 中表现出更高的摄取、保留和渗透潜力，克服了它们的高药物外排特性。此外，LCN 改善了福司可林的药代动力学参数，否则福司可林的保留率和生物利用度非常低。福司可林负载的 LCN 迫使 CSC 从它们的间充质状态退出，从而降低了它们的干性，并使它们对化疗敏感，同时抑制 E-钙粘蛋白介导的存活和肿瘤起始潜能，并逆转紫杉醇诱导的干性。我们进一步表明，在给予紫杉醇和福司可林共载 LCN 的原位异种移植小鼠模型后，纳米药物显示出增强的被动肿瘤靶向能力，具有很强的抗肿瘤活性，单次剂量即可消除小的实体瘤，并且在很长一段时间内没有肿瘤复发或全身毒性的迹象。总的来说，这些发现为一个概念提供了证据，即福司可林和紫杉醇在单一纳米制剂中的共递药可以实现整体肿瘤靶向，其中福司可林可以有效地重新编程/分化 CSC，而紫杉醇可以同时诱导分化的 CSC 和肿瘤细胞的细胞毒性。因此，这项研究可以提供一种纳米制剂，为癌症治疗提供一种有效的策略。
