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.

The development of synthetic strategies to produce statistical copolymers based on L-lactide (L-LA) and ε-caprolactone (CL), denoted as P(LA-stat-CL), remains highly challenging in polymer chemistry. This is due to the differing reactivity of the two monomers during their ring-opening copolymerization (ROcP). Yet, P(LA-stat-CL) materials are highly sought-after as they combine the properties of both polylactide PLA and poly(ε-caprolactone) (PCL). Here, benzoic acid (BA), a naturally occurring, cheap, readily recyclable and thermally stable weak acid, is shown to trigger the organocatalyzed ring-opening copolymerization (OROcP) of L-LA and CL under solvent-free conditions at 155 °C, in presence of various alcohols as initiators, with good control over molar masses and dispersities (1.11 <Đ< 1.35) of the resulting copolyesters. Various compositions can be achieved, and the formation of statistical compounds is shown through characterization by 1 H, 13 C and DOSY-NMR spectroscopies and by DSC, as well as through the determination of reactivity ratios (r LA = 0.86, r CL = 0.86), using the visualization of the sum of squared residuals space method. Furthermore, this BA-OROcP process can be exploited to access metal-free PLAb-P(LA-stat-CL)-b-PLA triblock copolymers, using a diol as initiator. Finally, residual traces of BA remaining in P(LA-stat-CL) copolymers (< 0.125 mol%) do not show any cytotoxicity towards hepatocyte-like HepaRG cells, demonstrating the safety of this organic catalyst.As biodegradable, nontoxic and biocompatible polymers, polylactide (PLA) and poly(εcaprolactone) (PCL) can be attractive biosourced surrogates for petroleum-based polymers. 1-4 Both PLA and PCL have been intensively investigated in applications ranging from pharmaceutics to packaging and electronics. 4-7 Yet, both PLA and PCL show some limitations in these applications.For instance, PLA is brittle, exhibits a poor elasticity, 8 a low thermal stability and a modest permeability to drugs. PCL has higher thermal stability and elasticity than PLA, with a glass transition temperature (T g ) around -60 °C vs. 45 -65 °C for PLA, 9,3,10 but suffers from poor mechanical properties. PCL has also a higher permeability to drugs 11 and a half time in vivo of 1year, 12 vs. a few weeks for PLA. 13 As a result, statistical copolymers of lactide (LA) and caprolactone (CL), i.e. P(LA-stat-CL) aliphatic copolyesters, are highly sought-after materials as they combine the strengths and minimize the weaknesses of both homopolymers. P(LA-stat-CL)s have thus attracted a great deal of attention in the biomedical and pharmaceutical fields, 14-18 and as compatibilizers for PLA/PCL blends. 19 The precision synthesis of P(LA-stat-CL) copolymers is still particularly challenging whether organometallic 20 or organic 21-30 catalysts are used. This is due to the highly differing reactivity of the two monomers during ring-opening copolymerization (ROcP). LA is typically incorporated first, although CL gives faster rates than LA in homopolymerization reactions. [21][...

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.