Poly(trimethylene carbonate)/Poly(malic acid) Amphiphilic Diblock Copolymers as Biocompatible Nanoparticles

Abstract

Amphiphilic polycarbonate-poly(hydroxyalkanoate) diblock copolymers, namely, poly(trimethylene carbonate) (PTMC)-b-poly(β-malic acid) (PMLA), are reported for the first time. The synthetic strategy relies on commercially available catalysts and initiator. The controlled ring-opening polymerization (ROP) of trimethylene carbonate (TMC) catalyzed by the organic guanidine base 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), associated with iPrOH as an initiator, provided iPrO-PTMC-OH, which served as a macroinitiator in the controlled ROP of benzyl β-malolactonate (MLABe) catalyzed by the neodymium triflate salt (Nd(OTf)3). The resulting hydrophobic iPrO-PTMC-b-PMLABe-OH copolymers were then hydrogenolyzed into the parent iPrO-PTMC-b-PMLA-OH copolymers. A range of well-defined copolymers, featuring different sizes of segments (Mn,NMR up to 9300 g mol(-1) ; ÐM =1.28-1.40), were thus isolated in gram quantities, as evidenced by NMR spectroscopy, size exclusion chromatography, thermogravimetric analysis, differential scanning calorimetry, and contact angle analyses. Subsequently, PTMC-b-PMLA copolymers with different hydrophilic weight fractions (11-75 %) self-assembled in phosphate-buffered saline upon nanoprecipitation into well-defined nano-objects with Dh =61-176 nm, a polydispersity index <0.25, and a negative surface charge, as characterized by dynamic light scattering and zeta-potential analyses. In addition, these nanoparticles demonstrated no significant effect on cell viability at low concentrations, and a very low cytotoxicity at high concentrations only for PTMC-b-PMLA copolymers exhibiting hydrophilic fractions over 47 %, thus illustrating the potential of these copolymers as promising nanoparticles.

Opsonisation of nanoparticles prepared from poly(β-hydroxybutyrate) and poly(trimethylene carbonate)-b-poly(malic acid) amphiphilic diblock copolymers: Impact on the in vitro cell uptake by primary human macrophages and HepaRG hepatoma cells

“…In this context, poly(3-hydroxybutyrate) and poly(trimethylene carbonate) have been developed to produce gels and matrices for tissue engineering (Shishatskaya et al, 2004 ;Asran et al, 2010 ;Song et al, 2011 ;Schüller-Ravoo et al, 2013 ;Rozila et al, 2016 ;Ding et al, 2016 ;Pascu et al, 2016 ;Zant et al, 2016) and NPs for drug delivery (Xiong et al, 2010 ;Jiang et al, 2013 ;Fukushima 2016 ;Pramual et al, 2016). Our laboratories have recently synthesized and characterized novel poly(hydroxyalkanoate)-based 7 amphiphilic diblock copolymers, namely poly(-malic acid)-b-poly(3-hydroxybutyrate) (PMLA-b-PHB) (Barouti et al, 2015) and poly(-malic acid)-b-poly(trimethylene carbonate) (PMLA-b-PTMC) (Barouti et al, 2016a), hydrophobic PMLA Be -b-PHB-b-PMLA Be and amphiphilic PMLA-b-PHB-b-PMLA triblock copolymers (Barouti et al, 2016b) as well as linear and star-shaped thermogelling poly([R]-3-hydroxybutyrate) copolymers (Barouti et al, 2016c). One of the objectives was to elaborate biocompatible and biodegradable copolymerbased NPs, and more importantly to highlight the impact of the chemical structure of the hydrophobic block and the influence of the hydrophilic weight fraction on the physico-chemical properties of the self-assembled systems.…”

Nanocomposites of Polymeric Biomaterials Containing Carbonate Groups: An Overview

“…In order to produce APC‐loaded NPs, ROP was employed to synthesize cyclic RGD peptide‐decorated polymeric micellar‐like NPs based on PEGylated PTMC (PEG‐PTMC) . PTMC‐ b ‐poly(b‐malic acid) NPs were synthesized via the nanoprecipitation method using a syringe pump . The selected BCP (1.2–10 mg) was dissolved in acetone (1 mL) and then it was added at 13.37 mL h −1 to a solution of phosphate‐buffered saline (2 mL) with 0.15 n NaCl at pH 7.4, under vigorous stirring (1300 rpm).…”

“…The selected BCP (1.2–10 mg) was dissolved in acetone (1 mL) and then it was added at 13.37 mL h −1 to a solution of phosphate‐buffered saline (2 mL) with 0.15 n NaCl at pH 7.4, under vigorous stirring (1300 rpm). After stirring of the suspension for 10 min, acetone was evaporated under vacuum . Moreover, the methoxy polyethylene glycol (mPEG)‐PTMC NPs were synthesized by ROP through the emulsion/solvent evaporation method according to the procedure explained in Jiang et al A family of amphiphilic sugar‐bearing BCPs was synthesized by metal‐free organocatalyzed ROP.…”

“…Polymeric biomaterials containing carbonate groups like aliphatic polycarbonates (APCs) have been widely used for drug delivery, theranostics, and tissue or bone engineering due to their biocompatibility, enzymatic degradability, and low toxicity . The APC‐based bio‐nanocomposites (NCs) have been shown to impart further strength: thermal stability while maintaining excellent biodegradability and biocompatibility are desired.…”

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

“…Consequently, many studies have been conducted to replace PEG by other hydrophilic blocks such as dextran [25] or poly(malic acid) [26][27][28]. Therefore, the synthesis of well-defined amphiphilic block copolymers constituted only by (bio)degradable and biocompatible polymers is of great interest.…”