Department of Pharmaceutical Technology, Faculty of Pharmacy & Biotechnology, the German University in Cairo, New Cairo, 11511, Egypt.
Department of Pharmaceutical Biology, Faculty of Pharmacy & Biotechnology, the German University in Cairo, New Cairo, 11511, Egypt.
Drug Deliv Transl Res. 2024 Feb;14(2):491-509. doi: 10.1007/s13346-023-01413-9. Epub 2023 Aug 23.
Despite the fact that chemoimmunotherapy has emerged as a key component in the era of cancer immunotherapy, it is challenged by the complex tumor microenvironment (TME) that is jam-packed with cellular and non-cellular immunosuppressive components. The aim of this study was to design a nanoparticulate system capable of sufficiently accumulating in the tumor and spleen to mediate local and systemic immune responses, respectively. The study also aimed to remodel the immunosuppressive TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered to simultaneously eradicate the cancer cells, silence the tumor-associated fibroblasts (TAFs), and re-educate the tumor-associated macrophages (TAMs) using doxorubicin, losartan, and metformin, respectively. These agents were also selected for their ability to tip the balance of the splenic immune cells towards immunostimulatory phenotypes. To establish TAM and TAF cultures, normal macrophages and fibroblasts were incubated with B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs were prepared, characterized, and tested in the target cell types. Organ distribution of fluorescein-loaded PLGA NPs was evaluated in a mouse model of melanoma. Finally, the local and systemic effects of different combination therapy programs were portrayed. The in vitro studies showed that the drug-loaded PLGA NPs could significantly ablate the immunosuppressive nature of Mel and skew TAMs and TAFs towards more favorable phenotypes. While in vivo, PLGA NPs were proven to exhibit long blood circulation time and to localize preferentially in the tumor and the spleen. The combination of either metformin or losartan with doxorubicin was superior to the monotherapy, both locally and systemically. However, the three-agent combo produced detrimental effects in the form of compromised well-being, immune depletion, and metastasis. These findings indicate the potential of TME remodeling as means to prime the tumors for successful chemoimmunotherapy. In addition, they shed light on the importance of the careful use of combination therapies and the necessity of employing dose-reduction strategies. D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded NPs, L-NPs losartan-loaded NPs, TAMs tumor-associated macrophages, TAFs tumor-associated fibroblasts, PD-L1 programmed death ligand 1, TNF-α tumor necrosis factor alpha, TGF-β transforming growth factor beta, CD206/40/86 cluster of differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases.
尽管化疗免疫疗法已成为癌症免疫治疗时代的关键组成部分，但它受到复杂肿瘤微环境（TME）的挑战，其中充满了细胞和非细胞免疫抑制成分。本研究旨在设计一种能够充分积聚在肿瘤和脾脏中的纳米颗粒系统，分别介导局部和全身免疫反应。本研究还旨在重塑免疫抑制性 TME。出于这些原因，多功能聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒（NPs）被设计成分别使用阿霉素、氯沙坦和二甲双胍来同时消灭癌细胞、沉默肿瘤相关成纤维细胞（TAFs）和重新教育肿瘤相关巨噬细胞（TAMs）。这些药物也被选择用于它们能够使脾脏免疫细胞的平衡向免疫刺激表型倾斜的能力。为了建立 TAM 和 TAF 培养物，正常巨噬细胞和成纤维细胞与 B16F10 黑色素瘤细胞（Mel）衍生的分泌组孵育。制备、表征载药 PLGA NPs，并在靶细胞类型中进行测试。在黑色素瘤小鼠模型中评估荧光素载药 PLGA NPs 的器官分布。最后，描述了不同联合治疗方案的局部和全身作用。体外研究表明，载药 PLGA NPs 可显著消除 Mel 的免疫抑制特性，并使 TAMs 和 TAFs 向更有利的表型倾斜。而在体内，PLGA NPs 被证明具有长血液循环时间，并优先定位于肿瘤和脾脏。与单独用药相比，二甲双胍或氯沙坦与阿霉素联合使用在局部和全身均具有优势。然而，三药联合在健康状况受损、免疫耗竭和转移的形式下产生了有害影响。这些发现表明，重塑 TME 作为为成功的化疗免疫疗法使肿瘤做好准备的一种手段具有潜力。此外，它们还揭示了仔细使用联合疗法的重要性，以及采用剂量减少策略的必要性。D-NPs 阿霉素载药 NPs、M-NPs 二甲双胍载药 NPs、L-NPs 氯沙坦载药 NPs、TAMs 肿瘤相关巨噬细胞、TAFs 肿瘤相关成纤维细胞、PD-L1 程序性死亡配体 1、TNF-α 肿瘤坏死因子 alpha、TGF-β 转化生长因子 beta、CD206/40/86 分化群 206/40/86、α-SMA alpha-smooth muscle actin、MMPs 基质金属蛋白酶。
