Cell Uptake and Biocompatibility of Nanoparticles Prepared from Poly(benzyl malate) (Co)polymers Obtained through Chemical and Enzymatic Polymerization in Human HepaRG Cells and Primary Macrophages.

Hubert Casajus,Sandrine Cammas-Marion,Manuel Vlach,Elise Vène,Pascal Loyer,Catherine Ribault,Caroline Nugier-Chauvin,Sylvain Tranchimand,Saad Saba,Eric Dubreucq,Nicolas Lepareur

doi:10.3390/polym10111244

Abstract

The design of drug-loaded nanoparticles (NPs) appears to be a suitable strategy for the prolonged plasma concentration of therapeutic payloads, higher bioavailability, and the reduction of side effects compared with classical chemotherapies. In most cases, NPs are prepared from (co)polymers obtained through chemical polymerization. However, procedures have been developed to synthesize some polymers via enzymatic polymerization in the absence of chemical initiators. The aim of this work was to compare the acute in vitro cytotoxicities and cell uptake of NPs prepared from poly(benzyl malate) (PMLABe) synthesized by chemical and enzymatic polymerization. Herein, we report the synthesis and characterization of eight PMLABe-based polymers. Corresponding NPs were produced, their cytotoxicity was studied in hepatoma HepaRG cells, and their uptake by primary macrophages and HepaRG cells was measured. In vitro cell viability evidenced a mild toxicity of the NPs only at high concentrations/densities of NPs in culture media. These data did not evidence a higher biocompatibility of the NPs prepared from enzymatic polymerization, and further demonstrated that chemical polymerization and the nanoprecipitation procedure led to biocompatible PMLABe-based NPs. In contrast, NPs produced from enzymatically synthesized polymers were more efficiently internalized than NPs produced from chemically synthesized polymers. The efficient uptake, combined with low cytotoxicity, indicate that PMLABe-based NPs are suitable nanovectors for drug delivery, deserving further evaluation in vivo to target either hepatocytes or resident liver macrophages.

Highlights

Biocompatible polymeric nanoparticles combined with the design of more specific therapeutic molecules are developed toward the goal of reducing the drug amounts administrated to patients, simplifying protocols of administration, and overcoming side effects
Taking advantage of the availability ofpolymers synthesized by polymerization in the presence of chemical initiators and enzymatic polymerization, the aim of this work was to compare the acute in vitro cytotoxicity of NPs prepared from PMLABe derivatives synthesized either by chemical (PMLABe chemicals) or enzymatic (PMLABe enzymatic) polymerization and their cell uptake
The three β-substituted β-lactones involved in this study were synthesized in four steps starting from DL, L, or D-aspartic acid, as described previously (Scheme 1) [32]

Summary

Introduction

Biocompatible polymeric nanoparticles combined with the design of more specific therapeutic molecules are developed toward the goal of reducing the drug amounts administrated to patients, simplifying protocols of administration, and overcoming side effects. (i) be biocompatible and/or (bio)degradable; (ii) be easy to produce in Good Manufacturing Practice (GMP) grade for clinical use; (iii) allow the encapsulation of a significant amount of active molecules such as drugs, genes, or peptides [8]; (iv) lead to the controlled release of active molecules at the targeted sites (cells, tissues, and/or organs) through the presence of targeting agents (antibodies, peptides, vitamins) [9,10,11]; and (v) have controlled surface characteristics to minimize their recognition by the immune system These nanovectors can take the form of active molecule–polymers conjugates [12], nanoparticles [13], micelles [14], or polymersomes [15]

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Methods

Conclusion