School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
Adv Drug Deliv Rev. 2018 May;130:3-11. doi: 10.1016/j.addr.2018.05.008. Epub 2018 May 18.
The justification of cancer nanomedicine relies on enhanced permeation (EP) and retention (R) effect and the capability of intracellular targeting due primarily to size after internalization (endocytosis) into the individual target cells. The EPR effect implies improved efficacy. Affinity targeting for solid tumors only occur after delivery to individual cells, which help internalization and/or retention. The design principles have been supported by animal results in numerous publications, but hardly translated. The natures of EP and R, such as frequency of large openings in tumor vasculature and their dynamics, are not understood, in particular, in clinical settings. Although various attempts to address the issues related to EP and delivery, by modifying design factors and manipulating tumor microenvironment, are being reported, they are still verified in artificial rodent tumors which do not mimic the nature of human tumor physiology/pathology in terms of transport and delivery. The clinical trials of experimental nanomedicine have experienced unexpected adverse effects with modest improvement in efficacy when compared to current frontline therapy. Future nanomedicine may require new design principles without consideration of EP and affinity targeting. A possible direction is to set new approaches to intentionally minimize adverse effects, rather than aiming at better efficacy, which can widen the therapeutic window of an anticancer drug of interest. Broadening indications and administration routes of developed therapeutic nanotechnology would benefit patients.
癌症纳米医学的合理性依赖于增强的渗透（EP）和保留（R）效应以及由于内化（内吞作用）进入单个靶细胞后的大小而具有的细胞内靶向能力。EPR 效应意味着提高了疗效。对实体瘤的亲和靶向仅在递送至单个细胞后发生，这有助于内化和/或保留。这些设计原则已得到许多出版物中动物实验结果的支持，但几乎没有转化。EP 和 R 的性质，例如肿瘤血管中大开口的频率及其动力学，尚不清楚，特别是在临床环境中。尽管通过修改设计因素和操纵肿瘤微环境来解决与 EP 和递送相关的问题的各种尝试正在被报道，但它们仍在人工啮齿动物肿瘤中得到验证，这些肿瘤在运输和递送方面都不能模拟人类肿瘤生理学/病理学的性质。与当前的一线治疗相比，实验性纳米医学的临床试验经历了意想不到的不良反应，疗效仅略有改善。未来的纳米医学可能需要新的设计原则，而无需考虑 EP 和亲和靶向。一种可能的方向是采用新方法来有意地最小化不良反应，而不是旨在提高疗效，这可以拓宽感兴趣的抗癌药物的治疗窗口。扩大已开发治疗性纳米技术的适应证和给药途径将使患者受益。
