Augmentation of EPR Effect and Efficacy of Anticancer Nanomedicine by Carbon Monoxide Generating Agents.

Jun Fang,Tomas Etrych,Karel Ulbrich,Vladimir Subr,Rayhanul Islam,Hongzhuan Yin,Waliul Islam,Hiroshi Maeda

doi:10.3390/pharmaceutics11070343

Abstract

One obstacle to the successful delivery of nanodrugs into solid tumors is the heterogeneity of an enhanced permeability and retention (EPR) effect as a result of occluded or embolized tumor blood vessels. Therefore, the augmentation of the EPR effect is critical for satisfactory anticancer nanomedicine. In this study, we focused on one vascular mediator involved in the EPR effect, carbon monoxide (CO), and utilized two CO generating agents, one is an extrinsic CO donor (SMA/CORM2 micelle) and another is an inducer of endogenous CO generation via heme oxygenase-1 (HO-1) induction that is carried out using pegylated hemin. Both agents generated CO selectively in solid tumors, which resulted in an enhanced EPR effect and a two- to three-folds increased tumor accumulation of nanodrugs. An increase in drug accumulation in the normal tissue did not occur with the treatment of CO generators. In vivo imaging also clearly indicated a more intensified fluorescence of macromolecular nanoprobe in solid tumors when combined with these CO generators. Consequently, the combination of CO generators with anticancer nanodrugs resulted in an increased anticancer effect in the different transplanted solid tumor models. These findings strongly warrant the potential application of these CO generators as EPR enhancers in order to enhance tumor detection and therapy using nanodrugs.

Highlights

Enhanced permeability and retention (EPR) effect is the basic concept for the tumor-targeted delivery of macromolecular anticancer agents [1,2]
It should be noted a very high level of carbon monoxide (CO) at 0 h in the liver is not coming from SMA/CORM2, but contributes to the endogenous heme oxygenase (HO) that is dominantly present in the liver, as it is the organ of heme degradation
We found significantly increased CO concentrations in the blood up until 2 h after the i.v. injection of SMA/CORM2 compared with the untreated control, and about a 1.5-time higher CO concentration was found in the liver after 4–8 h, but it was statistically insignificant; no apparent increases of CO amount in the other normal tissues were seen

Summary

Introduction

Enhanced permeability and retention (EPR) effect is the basic concept for the tumor-targeted delivery of macromolecular anticancer agents [1,2]. The advanced large tumors have many necrotic areas or degenerated blood vessels, and tumor blood flow is always irregular, so one can claim that the EPR effect exhibits a high degree of heterogeneity [5,6]. Because of such suppressed blood flow as seen by angiography, drug delivery to tumors is frequently very poor. The challenges to open-up tumor blood vessels and restore tumor blood flow are critical and of great importance for anticancer nanomedicine

Methods

Results

Discussion

Conclusion