Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors

Abstract

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines.

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

“…NP accumulation in tumors is a complex phenomenon, governed both by NP characteristics such as size, charge, and surface chemistry, as well as tumor properties such as vascular density, permeability, cell density, stromal content, etc . Heterogeneity in TME, even within tumors of same molecular subtype, poses a barrier to delivery and hence, therapeutic efficacy of macromolecular drugs such as antibodies and NPs.…”

Complex interplay between tumor microenvironment and cancer therapy

“…It has been well demonstrated that abnormal tumor vessels often grow rapidly to meet the nutrient demand to maintain tumor progression [141]. In this regard, disrupting the abnormal vascular system in TME could deplete the nutrition supply and induce tumor regression.…”

Tunable Hydrophile–Lipophile Balance for Manipulating Structural Stability and Tumor Retention of Amphiphilic Nanoparticles

“…Rational designs of nanomedicine aid in overcoming physiological barriers of solid tumors for achieving enhanced therapeutic efficacy, including manipulating physical, chemical, and biological properties of nanoparticles . Negatively charged nanoparticles (NPs) are very stable in the blood circulatory system, thereby allowing NPs accumulation in tumors through enhanced permeability and retention effects . It has been reported that the optimized size may also improve the delivery efficiency in tumors and NPs with moderate rigidity could enhance the multibiological barrier penetrating capability for drug delivery in comparison with their soft and hard counterparts .…”