Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis

Abstract

The innovative development of nanomedicine has promised effective treatment options compared to the standard therapeutics for cancer therapy. However, the efficiency of EPR-targeted nanodrugs is not always pleasing as it is strongly prejudiced by the heterogeneity of the enhanced permeability and retention effect (EPR). Targeting the dynamics of the EPR effect and improvement of the therapeutic effects of nanotherapeutics by using EPR enhancers is a vital approach to developing cancer therapy. Inadequate data on the efficacy of EPR in humans hampers the clinical translation of cancer drugs. Molecular targeting, physical amendment, or physiological renovation of the tumor microenvironment (TME) are crucial approaches for improving the EPR effect. Advanced imaging technologies for the visualization of EPR-induced nanomedicine distribution in tumors, and the use of better animal models, are necessary to enhance the EPR effect. This review discusses strategies to enhance EPR effect-based drug delivery approaches for cancer therapy and imaging technologies for the diagnosis of EPR effects. The effort of studying the EPR effect is beneficial, as some of the advanced nanomedicine-based EPR-enhancing approaches are currently undergoing clinical trials, which may be helpful to improve EPR-induced drug delivery and translation to clinics.

Keywords: EPR enhancers; EPR-based therapy; clinical trials; heterogeneity; nanomedicine; passive targeting; solid tumor.

Figure 1

Pharmacological approaches to improve EPR effect. (A). Vascular normalizer to improve the blood flow, (B). Fibrinolytics co-therapy, (C). Enhanced permeability of endothelial cells using vascular mediators, (D). Stromal density decreases by ECM degradation, (E). Tumor-penetrating peptides enhance transcytosis. Reprinted with permission from [23]. Copyright (2023), with permission from Elsevier.

Figure 2

Strategies to enhance EPR-based drug delivery targeting the tumor microenvironment. Adapted with permission from [17].

Figure 3

Imaging NP pharmacology and the EPR effect across multiple spatial and temporal scales. (A) Pharmacokinetics and pharmacodynamics (PK/PD) of NPs (B). Imaging strategies and (C) IVM modalities are particularly suitable for imagining dynamic and microscopic courses of the EPR effect and the TME. Adapted with permission from [18].