Yan Jianqin, Wei Dengshuai, Zhao Zijian, Sun Kaichuang, Sun Yong
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
Acta Biomater. 2025 Jan 24;193:474-483. doi: 10.1016/j.actbio.2024.12.048. Epub 2024 Dec 22.
Platinum (Pt)-based anticancer agents exhibit a lack of selectivity in the treatment of osteosarcoma, resulting in significant toxicity. Furthermore, immune surveillance withinthe tumor microenvironment impedes the uptake of platinum drugs by osteosarcoma cells. To overcome these challenges, an oxaliplatin-based Pt prodrug amphiphile (Lipo-OXA-ALN) was designed and synthesized by incorporatingan osteosarcoma-targeting alendronate (ALN) alongside a lipid tail. The lipid nanoparticles (ALN-OXA), which self-assemble from Lipo-OXA-ALN, enhanced intracellular platinum uptake due to their superior Ca trapping ability and significantly inhibit osteosarcoma cell activity. Moreover, ALN-OXA exhibited potent targeting capabilities, effectively suppressing osteosarcoma growth while preventing bone destruction. Importantly, ALN-OXA induces a series of immune responses characterized by the activation of immune cells, maturation of dendritic cells, and secretion of related cytokines, followed by the activation and infiltration of T lymphocytes and a significant increase in the ratio of cytotoxic T cells. Additionally, the ratio of M1/M2 macrophages increased markedly after ALN-OXA treatment, suggesting potential reprogramming of the tumor microenvironment by ALN-OXA. Overall, the improved therapeutic efficacy against osteosarcoma demonstrates that the Pt prodrug amphiphile represents a promising strategy for combining targeted chemotherapy with strategies aimed at reversing immune suppression. STATEMENT OF SIGNIFICANCE: Platinum (Pt)-based chemotherapy for osteosarcoma faces challenges due to poor tumor selectivity, leading to suboptimal efficacy and increased toxicity. Additionally, the osteosarcoma microenvironment impedes effective drug delivery. To overcome these limitations, we developed an oxaliplatin-based Pt prodrug nanoparticle (ALN-OXA) for targeted chemo-immunotherapy. ALN-OXA showed significant in vivo efficacy, effectively preventing bone damage and enhancing the immune microenvironment to improve treatment outcomes. This innovative approach not only targets the tumor more efficiently but also boosts immune response, offering a promising strategy for tumor blockade, tumor starvation, and other therapeutic applications in osteosarcoma treatment.
基于铂（Pt）的抗癌药物在骨肉瘤治疗中缺乏选择性，导致显著的毒性。此外，肿瘤微环境中的免疫监视阻碍了骨肉瘤细胞对铂类药物的摄取。为了克服这些挑战，通过将靶向骨肉瘤的阿仑膦酸盐（ALN）与脂质尾相结合，设计并合成了一种基于奥沙利铂的铂前药两亲物（Lipo-OXA-ALN）。由Lipo-OXA-ALN自组装形成的脂质纳米颗粒（ALN-OXA），由于其优异的钙捕获能力增强了细胞内铂的摄取，并显著抑制骨肉瘤细胞活性。此外，ALN-OXA表现出强大的靶向能力，有效抑制骨肉瘤生长，同时防止骨质破坏。重要的是，ALN-OXA诱导一系列免疫反应，其特征为免疫细胞的激活、树突状细胞的成熟以及相关细胞因子的分泌，随后T淋巴细胞激活并浸润，细胞毒性T细胞比例显著增加。此外，ALN-OXA处理后M1/M2巨噬细胞比例显著增加，表明ALN-OXA可能对肿瘤微环境进行重编程。总体而言，对骨肉瘤治疗效果的改善表明，铂前药两亲物代表了一种将靶向化疗与旨在逆转免疫抑制的策略相结合的有前景的策略。重要性声明：基于铂（Pt）的骨肉瘤化疗由于肿瘤选择性差而面临挑战，导致疗效欠佳和毒性增加。此外，骨肉瘤微环境阻碍了有效的药物递送。为了克服这些限制，我们开发了一种基于奥沙利铂的铂前药纳米颗粒（ALN-OXA）用于靶向化学免疫治疗。ALN-OXA在体内显示出显著疗效，有效防止骨质破坏并增强免疫微环境以改善治疗效果。这种创新方法不仅更有效地靶向肿瘤，还能增强免疫反应，为骨肉瘤治疗中的肿瘤阻断、肿瘤饥饿及其他治疗应用提供了一种有前景的策略。
