What Went Wrong with Anticancer Nanomedicine Design and How to Make It Right

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.