Synthesis of Poly(Dimethylmalic Acid) Homo- and Copolymers to Produce Biodegradable Nanoparticles for Drug Delivery: Cell Uptake and Biocompatibility Evaluation in Human Heparg Hepatoma Cells.

Ali Khalil,Manuel Vlach,Catherine Ribault,Sandrine Cammas-Marion,Olivier Coulembier,Saad Saba,Pascal Loyer

doi:10.3390/polym12081705

Abstract

Hydrophobic and amphiphilic derivatives of the biocompatible and biodegradable poly(dimethylmalic acid) (PdiMeMLA), varying by the nature of the lateral chains and the length of each block, respectively, have been synthesized by anionic ring-opening polymerization (aROP) of the corresponding monomers using an initiator/base system, which allowed for very good control over the (co)polymers’ characteristics (molar masses, dispersity, nature of end-chains). Hydrophobic and core-shell nanoparticles (NPs) were then prepared by nanoprecipitation of hydrophobic homopolymers and amphiphilic block copolymers, respectively. Negatively charged NPs, showing hydrodynamic diameters (Dh) between 50 and 130 nm and narrow size distributions (0.08 < PDI < 0.22) depending on the (co)polymers nature, were obtained and characterized by dynamic light scattering (DLS), zetametry, and transmission electron microscopy (TEM). Finally, the cytotoxicity and cellular uptake of the obtained NPs were evaluated in vitro using the hepatoma HepaRG cell line. Our results showed that both cytotoxicity and cellular uptake were influenced by the nature of the (co)polymer constituting the NPs.

Highlights

The field of nanotechnologies has grown exponentially in the past decades with the production of a plethora of nanoobjects for biomedical applications including drug delivery
The general objective of this work was to prepare biocompatible anddegradable macromolecular systems prepared frompolymers whose repeating units derive from dimethylmalic acid, a biocompatible and low molar mass molecule, by anionic ring-opening polymerization
The selected α,α,β-trisubstituted β-lactones were synthesized starting from diethyloxalpropionate, following a procedure initially described by Barbaud et al (Scheme 2) [35]

Summary

Introduction

The field of nanotechnologies has grown exponentially in the past decades with the production of a plethora of nanoobjects for biomedical applications including drug delivery. The rationale for drug delivery using nanoparticles (NPs) is based on the fact that most chemotherapies distribute evenly throughout the body resulting in low plasma drug concentration, limited bioavailability at the site where it is needed, rapid disposal, and side-effects in healthy organs [1]. The discovery of the enhanced permeability and retention (EPR) effect [3,4,5], defining the extravasation of nanovectors through the disorganized blood vessels within solid tumors, further supported the principle of drug-loaded NPs in rodent models of cancers, which opened perspectives for improving therapeutic indexes of vectorized chemotherapies [3,4,5]. Nanoparticles (NPs) having a wide range of chemistry and architecture (lipids or polymers nanocarriers, inorganic or viral NPs) have been proposed for cancer therapy and imaging [9,10]. Among all the developed NPs, those formulated from hydrophobic homopolymers and amphiphilic block copolymers present a real interest as a result of the versatility in the structure (homopolymers, block-copolymers, star-shaped (co)polymers, etc.) and chemistry (polyesters, polypeptides, polycyanoacrylates, etc.) of the constituting polymeric materials, which can be adjusted to the selected applications by modifying various parameters, including the monomers features, the polymerization procedure, the nature of end-chain and/or side-chain groups (chemical modifications) [7,11,12,13,14,15]

Objectives

Methods

Results

Conclusion