Sun Kaichuang, Wei Xiaodan, Han Shangcong, Sun Yong, Xiao Haihua, Wei Dengshuai
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
ACS Nano. 2025 Apr 8;19(13):13300-13313. doi: 10.1021/acsnano.5c00691. Epub 2025 Mar 4.
Platinum (Pt)-based chemotherapeutic agents, known for their potent cytotoxicity, are extensively used in clinical oncology. However, their therapeutic efficacy is severely limited by a variety of factors, particularly the hypoxic tumor microenvironment (TME), which not only impedes effective drug delivery but also triggers immune suppression, further diminishing the antitumor effects of Pt drugs. In response to these challenges, we have developed a biotin receptor (BR)-targeting oxaliplatin (OXA)-based Pt prodrug, named Lipo-OPt-BT, which could encapsulate hemoglobin (Hb) as an oxygen carrier, forming Pt-loaded lipid nanoparticles (Hb@BTOPt). The design of the Hb@BTOPt aims to address the dual issues of poor drug delivery and immune suppression by effectively increasing local oxygen tension in the TME. Notably, our findings demonstrate that the cytotoxic effects of the BR-targeting Pt prodrug and increased oxygen levels synergistically reverse the tumor immune microenvironment, leading to improved antitumor efficacy. We observed that Hb@BTOPt significantly improved the biodistribution of the drug, enabling it to preferentially accumulate in tumor regions. Importantly, the enhanced oxygenation within the TME also plays a critical role in reshaping the immune landscape of the tumor, promoting a more favorable immune environment for effective chemotherapy. This reversal of immune suppression is evidenced by increased infiltration of cytotoxic T cells and reduced levels of regulatory T cells (Tregs) within the tumor. These findings highlight the promising potential of using BR-targeting lipid Pt prodrug amphiphiles to improve drug accumulation at tumor sites and counteract immunosuppression induced by tumor hypoxia.
以其强大的细胞毒性而闻名的铂（Pt）基化疗药物在临床肿瘤学中被广泛使用。然而，它们的治疗效果受到多种因素的严重限制，特别是缺氧的肿瘤微环境（TME），它不仅阻碍了有效的药物递送，还引发免疫抑制，进一步削弱了铂类药物的抗肿瘤作用。为应对这些挑战，我们开发了一种靶向生物素受体（BR）的基于奥沙利铂（OXA）的铂前药，名为Lipo-OPt-BT，它可以包裹血红蛋白（Hb）作为氧载体，形成载铂脂质纳米颗粒（Hb@BTOPt）。Hb@BTOPt的设计旨在通过有效提高TME中的局部氧张力来解决药物递送不良和免疫抑制这两个双重问题。值得注意的是，我们的研究结果表明，靶向BR的铂前药的细胞毒性作用和增加的氧水平协同逆转肿瘤免疫微环境，从而提高抗肿瘤疗效。我们观察到Hb@BTOPt显著改善了药物的生物分布，使其能够优先在肿瘤区域积累。重要的是，TME内增强的氧合作用在重塑肿瘤免疫格局方面也起着关键作用，促进了更有利于有效化疗的免疫环境。肿瘤内细胞毒性T细胞浸润增加和调节性T细胞（Tregs）水平降低证明了这种免疫抑制的逆转。这些发现突出了使用靶向BR的脂质铂前药两亲物来改善药物在肿瘤部位的积累并对抗肿瘤缺氧诱导的免疫抑制的潜在前景。
