Reduction-Responsive Molecularly Imprinted Poly(2-isopropenyl-2-oxazoline) for Controlled Release of Anticancer Agents.

Michał Cegłowski,Valentin Victor Jerca,Richard Hoogenboom,Florica Adriana Jerca

doi:10.3390/pharmaceutics12060506

Michał Cegłowski, Valentin Victor Jerca + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics12060506

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Abstract

Trigger-responsive materials are capable of controlled drug release in the presence of a specific trigger. Reduction induced drug release is especially interesting as the reductive stress is higher inside cells than in the bloodstream, providing a conceptual controlled release mechanism after cellular uptake. In this work, we report the synthesis of 5-fluorouracil (5-FU) molecularly imprinted polymers (MIPs) based on poly(2-isopropenyl-2-oxazoline) (PiPOx) using 3,3′-dithiodipropionic acid (DTDPA) as a reduction-responsive functional cross-linker. The disulfide bond of DTDPA can be cleaved by the addition of tris(2-carboxyethyl)phosphine (TCEP), leading to a reduction-induced 5-FU release. Adsorption isotherms and kinetics for 5-FU indicate that the adsorption kinetics process for imprinted and non-imprinted adsorbents follows two different kinetic models, thus suggesting that different mechanisms are responsible for adsorption. The release kinetics revealed that the addition of TCEP significantly influenced the release of 5-FU from PiPOx-MIP, whereas for non-imprinted PiPOx, no statistically relevant differences were observed. This work provides a conceptual basis for reduction-induced 5-FU release from molecularly imprinted PiPOx, which in future work may be further developed into MIP nanoparticles for the controlled release of therapeutic agents.

Highlights

Cytotoxic drugs are used to treat cancer as they are primarily toxic to cells that are rapidly growing and dividing
The problems connected with their use mainly include relative lack of specificity during their biodistribution in the human body and side effects caused by the simultaneous attack of target cancer cells and healthy cells [1,2]. 5-Fluorouracil (5-FU) is a cytotoxic drug with a broad spectrum of activity against various tumors
We have shown that the synthesis of molecularly imprinted PiPOx with 5-FU can be performed using PiPOx and dicarboxylic acid

Summary

Introduction

Cytotoxic drugs are used to treat cancer as they are primarily toxic to cells that are rapidly growing and dividing. 5-FU undergoes fast metabolism in the human body, requiring a continuous administration of high doses during therapy, which leads to the occurrence of severe toxic effects in many patients [3,4,5]. To overcome these issues, 5-FU can be used with various drug delivery systems (DDS), which release it at the desired target site. 5-FU can be used with various drug delivery systems (DDS), which release it at the desired target site This allows for systemic toxicity to be reduced toward healthy cells and to localize 5-FU delivery only to selected tissue. Many 5-FU DDS have already been developed based on polymeric particles [6,7,8,9], hydrogels [10,11,12], magnetic nanoparticles [13,14,15], and clay minerals [16,17,18]

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