Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, School of Pharmacy, Abilene, TX, USA.
Laboratory of Experimental Oncology, Shaare Zedek Medical Center, Jerusalem, Israel.
J Control Release. 2018 Feb 10;271:139-148. doi: 10.1016/j.jconrel.2017.12.023. Epub 2017 Dec 23.
Liposomal nanoparticles are the most commonly used drug nano-delivery platforms. However, recent reports show that certain pegylated liposomal nanoparticles (PLNs) and polymeric nanoparticles have the potential to enhance tumor growth and inhibit antitumor immunity in murine cancer models. We sought herein to identify the mechanisms and determine whether PLN-associated immunosuppression and tumor growth can be reversed using alendronate, an immune modulatory drug. By conducting in vivo and ex vivo experiments with the immunocompetent TC-1 murine tumor model, we found that macrophages were the primary cells that internalized PLN in the tumor microenvironment and that PLN-induced tumor growth was dependent on macrophages. Treatment with PLN increased immunosuppression as evidenced by increased expression of arginase-1 in CD11bGr1 cells, diminished M1 functionality in macrophages, and globally suppressed T-cell cytokine production. Encapsulating alendronate in PLN reversed these effects on myeloid cells and shifted the profile of multi-cytokine producing T-cells towards an IFNγ perforin response, suggesting increased cytotoxic functionality. Importantly, we also found that PLN-encapsulated alendronate (PLN-alen), but not free alendronate, abrogated PLN-induced tumor growth and increased progression-free survival. In summary, we have identified a novel mechanism of PLN-induced tumor growth through macrophage polarization and immunosuppression that can be targeted and inactivated to improve the anticancer efficacy of PLN-delivered drugs. Importantly, we also determined that PLN-alen not only reversed protumoral effects of the PLN carrier, but also had moderate antitumor activity. Our findings strongly support the inclusion of immune-responsive tumor models and in-depth immune functional studies in the preclinical drug development paradigm for cancer nanomedicines, and the further development of chemo-immunotherapy strategies to co-deliver alendronate and chemotherapy for the treatment of cancer.
脂质体纳米粒是最常用的药物纳米递药平台。然而，最近的报告表明，某些聚乙二醇化的脂质体纳米粒（PLN）和聚合物纳米粒有可能增强小鼠癌症模型中的肿瘤生长并抑制抗肿瘤免疫。我们在此旨在确定机制，并确定是否可以使用免疫调节药物阿伦膦酸钠逆转 PLN 相关的免疫抑制和肿瘤生长。通过使用免疫功能正常的 TC-1 小鼠肿瘤模型进行体内和体外实验，我们发现巨噬细胞是肿瘤微环境中内化 PLN 的主要细胞，并且 PLN 诱导的肿瘤生长依赖于巨噬细胞。PLN 处理增加了免疫抑制，这表现在 CD11bGr1 细胞中精氨酸酶-1的表达增加，巨噬细胞中 M1 功能下降以及全局抑制 T 细胞细胞因子产生。用 PLN 包裹阿伦膦酸钠逆转了这些对髓样细胞的影响，并使多细胞因子产生 T 细胞的特征向 IFNγ穿孔素反应转移，表明增加了细胞毒性功能。重要的是，我们还发现 PLN 包裹的阿伦膦酸钠（PLN-alen），而不是游离的阿伦膦酸钠，可消除 PLN 诱导的肿瘤生长并增加无进展生存期。总之，我们已经确定了一种通过巨噬细胞极化和免疫抑制来诱导 PLN 诱导的肿瘤生长的新机制，该机制可以被靶向和失活，以提高 PLN 递送药物的抗癌功效。重要的是，我们还确定 PLN-alen 不仅逆转了 PLN 载体的促肿瘤作用，而且还具有中等的抗肿瘤活性。我们的研究结果强烈支持在癌症纳米医学的临床前药物开发范例中纳入免疫反应性肿瘤模型和深入的免疫功能研究，并进一步开发化学免疫治疗策略，以共同递送至阿伦膦酸钠和化疗治疗癌症。
