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A Selective-Tumor-Penetrating Strategy via Unidirectional Direct Transfer for Intravesical Therapy of Bladder Cancer.

Xiaowen QinHeng WangWentao XuBin ZhengHaibao ZhangQi ZhangYang LiuZhenghong LiuLi SunYixuan MouCenchao YaoWei ZhengYiyang ChenChenkai WangXuanyi ZhouYou-Qing ShenXiaowen QinDahong Zhang
Published in: Journal of medicinal chemistry (2024)
A selective tumor-penetrating strategy generally exploits tumor-targeted ligands to modify drugs so that the conjugate preferentially enters tumors and subsequently undergoes transcellular transport to penetrate tumors. However, this process shields ligands from their corresponding targets on the cell surface, possibly inducing an off-target effect during drug penetration at the tumor-normal interface. Herein, we first describe a selective tumor-penetrating drug (R11-phalloidin conjugates) for intravesical therapy of bladder cancer. The intravesical conjugates rapidly translocated across the mucus layer, specifically bound to tumors, and infiltrated throughout the tumor via direct intercellular transfer. Notably, direct transfer from normal cells to tumor cells was unidirectional because the pathways required for direct transfer, termed F-actin-rich tunneling nanotubes, were more unidirectionally extended from normal cells to tumor cells. Moreover, the intravesical conjugates displayed strong anticancer activity and well-tolerated biosafety in murine orthotopic bladder tumor models. Our study demonstrated the potential of a selective tumor-penetrating conjugate for effective intravesical anticancer therapy.
Keyphrases
  • muscle invasive bladder cancer
  • induced apoptosis
  • cancer therapy
  • stem cells
  • emergency department
  • spinal cord injury
  • oxidative stress
  • signaling pathway
  • drug delivery
  • cell cycle arrest
  • drug induced
  • pi k akt