Perspectives on the past, present, and future of cancer nanomedicine.

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.