Sun Duxin, Zhou Simon, Gao Wei
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
Clinical Pharmacology, Bristol Meyer Squibb Company, 86 Morris Avenue, Summit, New Jersey 07920, United States.
ACS Nano. 2020 Oct 27;14(10):12281-12290. doi: 10.1021/acsnano.9b09713. Epub 2020 Oct 6.
The three design criteria of anticancer nanomedicines to improve anticancer efficacy and to reduce toxicity have been debated for decades: (1) Nanomedicines increase drug accumulation through enhanced permeability and retention (EPR) in tumors to improve anticancer efficacy. (2) Long systemic circulation of nanomedicines with high plasma concentration reduces reticuloendothelial system (RES) clearance and decreases drug accumulation in the normal organs to reduce toxicity, and to enhance the EPR effect. (3) A universal nanodelivery platform based on EPR and long systemic circulation can be developed to deliver different anticancer drugs. Although these criteria have repeatedly been confirmed in preclinical xenograft cancers, the majority of anticancer nanomedicines have failed to improve clinical efficacy, while the clinical efficacies/safety of successful nanomedicines are inconsistent with these design criteria. First, the debate over tumor EPR may have mixed two different questions and missed more clinically relevant comparisons for nanomedicines versus free drugs. When tumors are compared with normal tissues, tumor EPR has been confirmed in both mouse xenograft tumors and human cancers. However, nanomedicines may not enhance drug accumulation in human tumors compared with free drugs, despite outstanding improvement in preclinical cancers. Heterogeneity of enhanced permeability and retention in human cancers occurs for small/large molecules and nanomedicines, which cannot fully explain the poor translation of nanomedicines' efficacy from preclinical cancer models to cancer patients. Second, long-circulation nanomedicine should not be used as a universal design criterion because it does not further improve tumor accumulation by tumor EPR in human patients nor universally reduce distribution in normal organs. In contrast, nanomedicines change the drug tissue distribution to alter anticancer efficacy/safety. Third, a universal nanodelivery platform that uses the same design criteria for different drugs is not feasible. Rather, drug-specific nanodelivery systems are required to overcome the intrinsic shortcomings of delivered drugs, which are determined by the physicochemical, pharmacokinetic, and pharmacodynamic properties of the delivered drugs and nanocarriers to improve their efficacy/safety.
为提高抗癌疗效并降低毒性，抗癌纳米药物的三项设计标准已争论了数十年：（1）纳米药物通过增强肿瘤的通透性和滞留性（EPR）来增加药物蓄积，从而提高抗癌疗效。（2）纳米药物在高血浆浓度下的长时间全身循环可减少网状内皮系统（RES）清除，并减少药物在正常器官中的蓄积，以降低毒性，并增强EPR效应。（3）可以开发基于EPR和长时间全身循环的通用纳米递送平台，以递送不同的抗癌药物。尽管这些标准在临床前异种移植癌症中已多次得到证实，但大多数抗癌纳米药物未能提高临床疗效，而成功的纳米药物的临床疗效/安全性与这些设计标准并不一致。首先，关于肿瘤EPR的争论可能混淆了两个不同的问题，并且错过了纳米药物与游离药物之间更多临床相关的比较。当将肿瘤与正常组织进行比较时，在小鼠异种移植肿瘤和人类癌症中均已证实肿瘤EPR。然而，尽管在临床前癌症中有显著改善，但与游离药物相比，纳米药物可能不会增加在人类肿瘤中的药物蓄积。人类癌症中增强的通透性和滞留性在小分子/大分子以及纳米药物中存在异质性，这无法完全解释纳米药物疗效从临床前癌症模型到癌症患者的不佳转化。其次，长循环纳米药物不应被用作通用的设计标准，因为它不会通过人类患者的肿瘤EPR进一步改善肿瘤蓄积，也不会普遍减少在正常器官中的分布。相反，纳米药物会改变药物的组织分布，从而改变抗癌疗效/安全性。第三，对不同药物使用相同设计标准的通用纳米递送平台是不可行的。相反，需要药物特异性纳米递送系统来克服所递送药物的固有缺点，这些缺点由所递送药物和纳米载体的物理化学、药代动力学和药效学性质决定，以提高其疗效/安全性。
