Abstract：
Platinum(II)-based drugs (PtII), which hinder DNA replication, are the most widely used chemotherapeutics. However, current PtII drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (PtIV) prodrug amphiphile (C16-OPtIV-R8K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R8K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPtIV) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPtIV\'s bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPtIV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPtIV recruited more CD4+ and CD8+ T cells and reduced CD4+ Foxp3+ Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy.
摘要：
以铂（II）为基础的药物（PtII），阻碍DNA复制，是最广泛使用的化疗药物。然而,目前的PtII药物经常错过它们的DNA靶标，导致严重的副作用和耐药性。为了克服这一挑战，我们开发了一种新型的奥沙利铂（IV）（PtIV）前药两亲物（C16-OPtIV-R8K），整合长链疏水脂质和靶向核的亲水肽（R8K）。这种设计允许前药自组装成高度均匀的脂质纳米颗粒(NTPtIV),用于增强靶向化疗和免疫疗法。随后，NTPtIV的生物活性和效应在不同的水平上进行了检查，包括癌细胞，3D肿瘤球，和体内。我们的体外研究表明，74%的铂类药物的癌细胞核定位比奥沙利铂高3.6倍，在消除耐药癌细胞方面实现了十倍以上的增长。在体内,NTPtIV显示有效的肿瘤积累，导致小鼠乳腺癌的肿瘤生长受到抑制。此外，NTPtIV招募更多的CD4+和CD8+T细胞，减少CD4+Foxp3+Tregs，协同增强靶向化疗和免疫治疗。总的来说,这种策略在核靶向癌症治疗中取得了有希望的进展，协同提高化疗和免疫治疗的疗效。
