Wang Rong, Wang Ke, Li Zhuolin, Long Haoping, Zhang Dongyu, Li Yanting, Xia Zhuolu, Guo Xindong, Chen Wei, Cao Feng, Jiang Feng
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, P. R. China.
Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China.
ACS Appl Mater Interfaces. 2025 May 7;17(18):27434-27447. doi: 10.1021/acsami.5c02384. Epub 2025 Apr 27.
Gemcitabine (GTB), a clinically approved nucleoside analogue for cancer treatment, faces therapeutic limitations due to rapid enzymatic deactivation by cytidine deaminase (CDA) in tumor microenvironments. Over 90% of systemically administered GTB undergoes catalytic conversion to inactive 2'-deoxy-2',2'-difluorouracil metabolites through CDA-mediated deamination. To address this pharmacological challenge, we developed a multifunctional codelivery nanosystem through strategic engineering of reactive oxygen species (ROS)-generating, mitochondria-targeting CPUL1-TPP (CT) nanoaggregates. These self-assembling CT/GTB complexes were further optimized with DSPE-MPEG2k (DP) and Angiopep-2-conjugated DSPE-MPEG2k (Ang-DP) to create blood-brain barrier (BBB)-penetrating Ang-DP@CT/GTB nanoparticles, enhancing both physiological stability and low-density lipoprotein receptor-related protein 1 (LRP1)-mediated glioma targeting. Comparative analyses revealed that Ang-DP@CT/GTB nanoparticles significantly enhanced GTB's antiglioblastoma efficacy compared to free drug administration in both and models. Mechanistic investigations demonstrated that the nanosystem upregulates heme oxygenase-1 (HO-1), subsequently downregulating CDA expression to mitigate GTB metabolism. This coordinated molecular modulation prolongs GTB's therapeutic activity while leveraging the ROS-generating capacity of CT components for synergistic tumor suppression. The BBB-permeable codelivery platform exemplifies a rational design paradigm for multifunctional carrier-free pure nanodrugs (PNDs), demonstrating how clinical drug reformulation can overcome inherent pharmacokinetic limitations. This nanotechnology-driven approach provides critical insights for optimizing chemotherapeutic performance through metabolic pathway regulation and targeted delivery engineering.
吉西他滨（GTB）是一种临床上已获批准用于癌症治疗的核苷类似物，但由于肿瘤微环境中的胞苷脱氨酶（CDA）能迅速使其发生酶促失活，因而面临治疗局限性。超过90%经全身给药的GTB会通过CDA介导的脱氨作用催化转化为无活性的2'-脱氧-2',2'-二氟尿嘧啶代谢物。为应对这一药理学挑战，我们通过对产生活性氧（ROS）、靶向线粒体的CPUL1-TPP（CT）纳米聚集体进行策略性工程设计，开发了一种多功能共递送纳米系统。这些自组装的CT/GTB复合物进一步用DSPE-MPEG2k（DP）和与血管生成素-2偶联的DSPE-MPEG2k（Ang-DP）进行优化，以制备穿透血脑屏障（BBB）的Ang-DP@CT/GTB纳米颗粒，增强生理稳定性以及低密度脂蛋白受体相关蛋白1（LRP1）介导的胶质瘤靶向性。比较分析表明，在 和 模型中，与游离药物给药相比，Ang-DP@CT/GTB纳米颗粒显著增强了GTB的抗胶质母细胞瘤疗效。机制研究表明，该纳米系统上调血红素加氧酶-1（HO-1），随后下调CDA表达以减轻GTB代谢。这种协同的分子调节延长了GTB的治疗活性，同时利用CT组分的产生活性氧能力实现协同肿瘤抑制。这种可穿透血脑屏障的共递送平台体现了多功能无载体纯纳米药物（PND）的合理设计范例，展示了临床药物重新配方如何克服固有的药代动力学局限性。这种纳米技术驱动的方法为通过代谢途径调节和靶向递送工程优化化疗性能提供了关键见解。
