Cisplatin delivery vehicles based on stabilized polymeric aggregates comprising poly(acrylic acid) chains

Ekaterina Stoyanova,Neli Koseva,Georgi Momekov,Petar Petrov,Irina Karadjova

doi:10.1038/pj.2017.29

Abstract

Stabilized polymeric aggregates (SPAs) comprising poly(acrylic acid) (PAA) chains were studied as a delivery platform for cisplatin. SPAs were prepared by blending a poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) triblock copolymer with a poly(acrylic acid)-block-poly(propylene oxide)-block-poly(acrylic acid) triblock copolymer and additional loading and photocrosslinking of pentaerythritol tetraacrylate (PETA). Dynamic light scattering analysis revealed particles with a hydrodynamic diameter of 176 nm and a monomodal particle size distribution. The stabilized polymeric aggregates were loaded with cisplatin by a ligand exchange reaction, achieving a high loading efficiency of 76%. A study on the release of complexes of platinum(II) from the particles in phosphate-buffered saline (PBS) and citrate buffer solution (CBS) at 37 °C revealed a sustained release profile. More than 90% and nearly 80% of the loaded drug were released within 312 h in PBS and CBS, respectively. The in vitro cell viability assay indicated that cisplatin immobilized in the SPAs is less cytotoxic than the non-immobilized agent. The intracellular accumulation of the entrapped complex was comparable to that of the free drug. Complexation of cisplatin with stabilized ‘Pluronic’ aggregates, containig functional poly(acrylic acid) moieties was investigated as platform for drug delivery application. The advantageous characteristics of the system involve high drug payload, excellent stability upon storage and sustained drug release of the conjugated drug over 2 weeks.

Highlights

The use of polymeric nanocarriers for drug delivery has shown significant therapeutic potential to improve the efficiency and specificity of the drug action
Synthesis of stabilized polymeric aggregates An amphiphilic ABA triblock copolymer with a central poly(propylene oxide) (PPO) block and two outer poly(acrylic acid) blocks was synthesized by atom transfer radical polymerization (ATRP) of tBA and subsequent hydrolysis of poly(tert-butyl acrylate) (PtBA) blocks
The PtBA-PPO-PtBA copolymer was derivatized into poly(acrylic acid) (PAA)-PPO-PAA by hydrolysis of the outer PtBA blocks with five equivalents of trifluoroacetic acid with respect to the tBA-units according to a known procedure.[31]

Summary

Introduction

The use of polymeric nanocarriers for drug delivery has shown significant therapeutic potential to improve the efficiency and specificity of the drug action. Cis-dichlorodiamminoplatinum(II) (cisplatin) is one of the most potent anticancer drugs and is widely used in the treatment of many solid tumors.[1] disadvantages, including severe side effects, are a short circulation period in the blood due to glomerular excretion and intrinsic or acquired resistance of some tumors to the drug, limit its clinical application.[2,3] The drawbacks of therapy with cisplatin have stimulated an intensive search for less toxic alternatives, mainly focusing on the development of various drug delivery systems, including water-soluble polymers,[4,5,6,7] long-circulating liposomes[8,9,10] and polymeric micelles.[11,12,13]. It has been established that polymeric micelles accumulate to a higher extent in solid tumors than larger nanoparticles like liposomes.[16]

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Conclusion