Key Laboratory of Smart Biomaterials of Zhejiang Province and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China; Department of Cell Biology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China.
Department of Cell Biology, School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China.
Adv Drug Deliv Rev. 2022 Oct;189:114480. doi: 10.1016/j.addr.2022.114480. Epub 2022 Aug 8.
Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedicines, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can confer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospectthe development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clinical translation.
外渗是循环中的纳米药物到达靶向实体瘤的第一步。传统的纳米药物被设计为通过先前假设富含肿瘤血管的内皮细胞间隙渗透到肿瘤间质中，即增强的通透性和保留（EPR）效应。虽然 EPR 效应已在动物异种移植肿瘤模型中得到验证，但越来越多的证据表明，EPR 效应在人类肿瘤中非常有限且高度异质，导致纳米药物的外渗极不可预测且效率低下，从而限制了其治疗效果，包括已在临床上批准的纳米药物。实现不依赖 EPR 的外渗是开发新一代高效纳米药物的关键。肿瘤内皮细胞的转胞吞作用可以使纳米药物主动外渗到实体瘤中，而不依赖于 EPR 效应。在这里，我们综述和展望了转胞吞作用诱导的纳米药物的发展，希望为设计能够选择性地穿过肿瘤内皮细胞进行跨细胞转运的纳米药物提供有指导意义的见解，从而激发下一代用于临床转化的纳米药物的发展。
