Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship.

Braunová Braunová,Šírová Šírová,Kaňa Kaňa,Kostka Kostka,Kudláčová Kudláčová,Etrych Etrych,Betka Betka,Bouček Bouček

doi:10.3390/pharmaceutics11110579

Abstract

Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) as potential macromolecular inhibitors of P-gp, and concurrently, carriers of drugs, passively targeting solid tumors by the enhanced permeability and retention (EPR) effect. Interestingly, there were significant differences between the effects of di- and tri- block polymer-based micelles, with the former being significantly more thermodynamically stable and showing much higher P-gp inhibition ability. The presence of Boc-protected hydrazide groups or the Boc-deprotection method did not affect the physico-chemical or biological properties of the block copolymers. Moreover, diblock polymer micelles could be loaded with free PPO containing 5–40 wt % of free PPO, which showed increased P-gp inhibition in comparison to the unloaded micelles. Loaded polymer micelles containing more than 20 wt % free PPO showed a significant increase in toxicity; thus, loaded diblock polymer micelles containing 5–15 wt % free PPO are potential candidates for in vitro and in vivo application as potent MDR inhibitors and drug carriers.

Highlights

Malignant neoplasms are life-threatening and devastating human diseases
The intracellular concentration of the drug is reduced to subtherapeutic levels due to P-gp activity before the drug can fulfil its mission within the tumor cells, thereby reducing the efficacy of chemotherapy in cancer treatment [4]
By the co-administration of P-gp inhibitors with anticancer drugs; such low molecular weight (LMW) inhibitors of P-gp include verapamil, cyclosporine A, ritonavir, or reversin [4]. These compounds have several disadvantages, e.g., short circulation in the blood and non-selective biodistribution, which lead to serious side effects on healthy cells, e.g., liver hepatocytes with increased P-gp level [4]

Summary

Introduction

Malignant neoplasms are life-threatening and devastating human diseases. To improve the anti-tumor efficiency of low molecular weight (LMW) anticancer drugs, various drug delivery systems and polymer-based prodrugs have been designed and investigated in preclinical and clinical trials [1]. There is an effort to overcome MDR by the co-administration of P-gp inhibitors with anticancer drugs; such LMW inhibitors of P-gp include verapamil, cyclosporine A, ritonavir, or reversin [4] These compounds have several disadvantages, e.g., short circulation in the blood and non-selective biodistribution, which lead to serious side effects on healthy cells, e.g., liver hepatocytes with increased P-gp level [4]. These drawbacks can be overcome either by covalent or non-covalent attachment of the inhibitors to high molecular weight (HMW) polymer carriers, alone or in combination with anticancer drugs [7,8,9]. Triblock amphiphilic copolymers of poly(ethylene glycol) (PEG) and PPO, have been extensively studied as polymer carriers of non-covalently attached hydrophobic drugs (doxorubicin, taxols) as well as micellar HMW polymer inhibitors

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