title: Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers.
abstract: Polyesters are extensively used in drug delivery because of their controllable biodegradation properties and perceived favorable cytocompatibility. However, new ester-based materials are continually being sought which can be produced from readily accessible monomers, which can be tuned for drug encapsulation and which retain good cellular compatibilities. In this study, 5 polyesters of similar molar mass were synthesized by reacting 1,10-decanediol with different ratios of succinic acid/phenylsuccinic acid and the effect of the phenyl side-chain group addition on polymer properties relevant to drug delivery was investigated. A polymer with a 70/30 ratio of succinic acid and phenylsuccinic acid was selected based on its ability to encapsulate a model dye in nanoparticle (NP) formulations, and was found to be slowly degradable in phosphate buffered saline (PBS) but more rapidly degraded in the presence of a lipase. The compatibility of NP formulations of this polymer either with or without a Pluronic F68 stabilizing coating was assessed in vitro using the C3A hepatocyte cell line. Cell viability was assessed, at NP concentrations ranging from 4.68-300μgmL-124h post-exposure, using the Alamar Blue, CDFA and Neutral Red assays. C3A cells internalized both coated and uncoated polyester NPs to a similar extent, with uptake observed to increase over time (10-1440min). Although cell viability was >80% at the concentrations tested, in all assays, it was found that a Pluronic F68 coated poly (decanediol-phenylsuccinate-co-succinate) stimulated significant DNA damage driven by an oxidant mechanism, whereas the non-coated polyester analogue and the Pluronic F68 alone had no effect. The results obtained suggest that new polyesters can be synthesized with desirable properties from the materials perspective but formulation with additional excipients requires careful evaluation for drug delivery applications.
authors: School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK.
authors: Deepak
authors: D
authors: Kakde
authors: School of Engineering and Physical Sciences, Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, UK.
authors: Leagh G
authors: LG
authors: Powell
authors: School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK.
authors: Kuldeep K
authors: KK
authors: Bansal
authors: School of Chemistry, University of Nottingham, University Park, Nottingham NG72RD, UK.
authors: Steve
authors: S
authors: Howdle
authors: Department of Chemical and Environmental, Faculty of Engineering, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors: Derek
authors: D
authors: Irvine
authors: School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK.
authors: Giuseppe
authors: G
authors: Mantovani
authors: School of Engineering and Physical Sciences, Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, UK.
authors: Gavin
authors: G
authors: Millar
authors: Institute of Pharmaceutical Technology and Biopharmaceutics, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, D-06120 Halle/Saale, Germany.
authors: Lea Ann
authors: LA
authors: Dailey
authors: School of Engineering and Physical Sciences, Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, UK.
authors: Vicki
authors: V
authors: Stone
authors: School of Engineering and Physical Sciences, Nano Safety Research Group, Heriot-Watt University, Edinburgh EH14 4AS, UK. Electronic address: H.Johnston@hw.ac.uk.
authors: Helinor J
authors: HJ
authors: Johnston
authors: School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK. Electronic address: cameron.alexander@nottingham.ac.uk.
authors: Cameron
authors: C
authors: Alexander
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry; D004249:DNA Damage; D005233:Fatty Alcohols / Q000737:chemistry; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D020442:Poloxamer / Q000008:administration & dosage / Q000737:chemistry; D011091:Polyesters / Q000008:administration & dosage* / Q000737:chemistry; D013386:Succinates / Q000737:chemistry; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry
chemical_list: C508606:CXCL8 protein, human; D003374:Coumarins; D005233:Fatty Alcohols; D005456:Fluorescent Dyes; D016209:Interleukin-8; D011091:Polyesters; D013386:Succinates; D013844:Thiazoles; C517282:coumarin 6; D020442:Poloxamer; C118975:1,10-decanediol
keywords: Cytotoxicity; Hepatocyte; In vitro; Nanoparticles; Polycondensation; Polyester; Polymer; Uptake