El-Hefnawy Nour-Elhoda, Youssef Magdy M, Abol-Enein Hassan, Gabal Raghda Abo
Department of Chemistry, Biochemistry Division, Faculty of Science, Mansoura University, Mansoura, Egypt.
Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt.
Sci Rep. 2025 Jul 2;15(1):23138. doi: 10.1038/s41598-025-06965-z.
Bladder cancer remains a major clinical challenge due to high recurrence rates, metastatic potential, and the development of drug resistance driven by complex gene regulation. Targeting the PI3K/AKT/mTOR pathway is a promising strategy, as its dysregulation promotes tumor growth and survival. Rapamycin, Everolimus, Temsirolimus and Other ATP-competitive inhibitors work by binding to the mTOR protein and preventing it from activating downstream signaling pathways that control cell growth and division. However, the therapeutic potential of Rapamycin, an mTORC1 inhibitor, is limited by poor solubility, low bioavailability, and non-specific distribution. This study explores the use of poly (lactic-co-glycolic acid) nanoparticles to encapsulate Rapamycin for enhanced delivery and controlled release in bladder cancer therapy. Drug release followed the Korsmeyer-Peppas model, indicating sustained release behavior. In vitro cytotoxicity assays demonstrated that Rapa-PLGA NPs significantly reduced the IC50 compared to free Rapamycin in T24 bladder cancer cells. Wound healing assays revealed substantial inhibition of cancer cell migration. Gene expression analysis showed that Rapa-PLGA NPs effectively downregulated mTOR, HIF-α, BCL-2, and ABCC1, while upregulating FOXO1 and MAPK, promoting apoptosis and reducing drug resistance. These findings highlight the potential of Rapa-PLGA NPs to enhance Rapamycin's therapeutic efficacy by integrating nanotechnology-driven delivery with gene regulatory mechanisms. This nanoparticle-based system presents a promising strategy for improving targeted bladder cancer therapy and overcoming drug resistance, warranting further in vivo investigation.
由于膀胱癌具有高复发率、转移潜能以及由复杂基因调控驱动的耐药性发展，它仍然是一个重大的临床挑战。靶向PI3K/AKT/mTOR通路是一种有前景的策略，因为其失调会促进肿瘤生长和存活。雷帕霉素、依维莫司、替西罗莫司和其他ATP竞争性抑制剂通过与mTOR蛋白结合起作用，阻止其激活控制细胞生长和分裂的下游信号通路。然而，mTORC1抑制剂雷帕霉素的治疗潜力受到溶解度差、生物利用度低和非特异性分布的限制。本研究探索使用聚（乳酸-乙醇酸）纳米颗粒包裹雷帕霉素，以增强其在膀胱癌治疗中的递送和控释。药物释放遵循Korsmeyer-Peppas模型，表明具有持续释放行为。体外细胞毒性试验表明，与游离雷帕霉素相比，Rapa-PLGA纳米颗粒在T24膀胱癌细胞中显著降低了IC50。伤口愈合试验显示对癌细胞迁移有显著抑制作用。基因表达分析表明，Rapa-PLGA纳米颗粒有效下调了mTOR、HIF-α、BCL-2和ABCC1，同时上调了FOXO1和MAPK，促进细胞凋亡并降低耐药性。这些发现突出了Rapa-PLGA纳米颗粒通过将纳米技术驱动的递送与基因调控机制相结合来增强雷帕霉素治疗效果的潜力。这种基于纳米颗粒的系统为改善靶向膀胱癌治疗和克服耐药性提供了一种有前景的策略，值得进一步进行体内研究。
