Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India.
Department of Biological Sciences, School of Life Science and Biotechnology, Adamas University, Kolkata, 700126, West Bengal, India.
J Nanobiotechnology. 2024 May 25;22(1):285. doi: 10.1186/s12951-024-02518-0.
Therapeutic management of locally advanced and metastatic triple negative breast cancer (TNBC) is often limited due to resistance to conventional chemotherapy. Metastasis is responsible for more than 90% of breast cancer-associated mortality; therefore, the clinical need to prevent or target metastasis is immense. The epithelial to mesenchymal transition (EMT) of cancer stem cells (CSCs) is a crucial determinant in metastasis. Doxorubicin (DOX) is the frequently used chemotherapeutic drug against TNBC that may increase the risk of metastasis in patients. After cancer treatment, CSCs with the EMT characteristic persist, which contributes to advanced malignancy and cancer recurrence. The latest developments in nanotechnology for medicinal applications have raised the possibility of using nanomedicines to target these CSCs. Hence, we present a novel approach of combinatorial treatment of DOX with dietary indole 3,3'-diindolylmethane (DIM) which is an intriguing field of research that may target CSC mediated EMT induction in TNBC. For efficient delivery of both the compounds to the tumor niche, advance method of drug delivery based on exosomes sheathed with mesoporous silica nanoparticles may provide an attractive strategy.
DOX, according to our findings, was able to induce EMT in CSCs, making the breast cancer cells more aggressive and metastatic. In CSCs produced from spheres of MDAMB-231 and 4T1, overexpression of N-cadherin, Snail, Slug, and Vimentin as well as downregulation of E-cadherin by DOX treatment not only demonstrated EMT induction but also underscored the pressing need for a novel chemotherapeutic combination to counteract this detrimental effect of DOX. To reach this goal, DIM was combined with DOX and delivered to the CSCs concomitantly by loading them in mesoporous silica nanoparticles encapsulated in exosomes (e-DDMSNP). These exosomes improved the specificity, stability and better homing ability of DIM and DOX in the in vitro and in vivo CSC niche. Furthermore, after treating the CSC-enriched TNBC cell population with e-DDMSNP, a notable decrease in DOX mediated EMT induction was observed.
Our research seeks to propose a new notion for treating TNBC by introducing this unique exosomal nano-preparation against CSC induced EMT.
局部晚期和转移性三阴性乳腺癌（TNBC）的治疗管理通常受到常规化疗耐药性的限制。转移是导致 90%以上乳腺癌相关死亡的原因；因此，预防或靶向转移的临床需求非常巨大。癌症干细胞（CSC）的上皮间质转化（EMT）是转移的关键决定因素。阿霉素（DOX）是常用于治疗 TNBC 的化疗药物，可能会增加患者发生转移的风险。癌症治疗后，具有 EMT 特征的 CSCs 持续存在，这导致恶性程度更高和癌症复发。医学应用纳米技术的最新进展提高了使用纳米药物靶向这些 CSCs 的可能性。因此，我们提出了一种新的 DOX 与膳食吲哚 3,3'-二吲哚基甲烷（DIM）联合治疗的方法，这是一个有趣的研究领域，可能针对 TNBC 中 CSC 介导的 EMT 诱导。为了有效地将这两种化合物递送到肿瘤微环境中，基于包裹有介孔硅纳米粒子的外体的先进药物递送方法可能提供一种有吸引力的策略。
根据我们的发现，DOX 能够诱导 CSCs 中的 EMT，使乳腺癌细胞更具侵袭性和转移性。在 MDAMB-231 和 4T1 球体产生的 CSCs 中，DOX 处理不仅上调了 N-钙粘蛋白、Snail、Slug 和波形蛋白，下调了 E-钙粘蛋白，证明了 EMT 的诱导，而且强调了迫切需要一种新的化疗联合来对抗 DOX 的这种有害作用。为了达到这个目标，DIM 与 DOX 联合，并通过将它们装载到包裹在外体中的介孔硅纳米粒子中（e-DDMSNP）同时递送到 CSCs 中。这些外体提高了 DIM 和 DOX 在体外和体内 CSC 微环境中的特异性、稳定性和更好的归巢能力。此外，在用 e-DDMSNP 处理富含 CSC 的 TNBC 细胞群后，观察到 DOX 介导的 EMT 诱导明显减少。
我们的研究旨在通过引入这种针对 CSC 诱导的 EMT 的独特外体纳米制剂，为治疗 TNBC 提出一个新概念。
