Biocompatibility and Physiological Thiolytic Degradability of Radically Made Thioester-Functional Copolymers: Opportunities for Drug Release (original) (raw)
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2022
Being non-degradable, vinyl polymers have limited biomedical applicability. Unfortunately, backbone esters incorporated through conventional radical ring-opening methods do not undergo appreciable abiotic hydrolysis under physiologically relevant conditions. Here, PEG acrylate and di(ethylene glycol) acrylamide-based copolymers containing backbone thioesters were prepared through the radical ring-opening copolymerization of the thionolactone dibenzo[c,e]oxepin-5(7H)-thione. The thioesters degraded fully in the presence of 10 mM cysteine at pH 7.4, with the mechanism presumed to involve an irreversible S–N switch. Degradations with N-acetylcysteine and glutathione were reversible through the thiol–thioester exchange polycondensation of R–SC(=O)–polymer–SH fragments with full degradation relying on an increased thiolate:thioester ratio. Treatment with 10 mM glutathione at pH 7.2 (mimicking intracellular conditions) triggered an insoluble–soluble switch of a temperature-responsive copo...
The radical thiocarbonyl addition–ring-opening (TARO) copolymerization of thionolactones with vinyl comonomers affords selectively degradable thioester functional polymers promising for biomedical applications. Herein, the use of atom transfer radical polymerization (ATRP) is investigated for the first time, using dibenzo[c,e]oxepane-5(7H)-thione (DOT), Cu(I)Br, and tris[2-(dimethylamino)ethyl]amine (Me6TREN) as thionolactone, catalyst, and ligand, respectively, with the acrylate comonomers poly(ethylene glycol) methyl ether acrylate (PEGA), methyl acrylate, benzyl acrylate, and butyl acrylate. Polymerizations were impeded by a side reaction, the Cu(I)-catalyzed dethionation of DOT to its (oxo)lactone analog, which caused the loss of up to 50 mol% of DOT in the early polymerization stages and limited the final copolymer DOT content. Nonetheless, readily degradable copolymers with low dispersities (1.10 ≤ Ð ≤ 1.26) were formed using DMSO, acetonitrile, or toluene as solvent. Presumin...
ACS applied polymer materials, 2020
Radical ring-opening polymerization is a clever strategy to incorporate cleavable linkages into otherwise non-degradable vinyl polymers. But conventional systems suffer from slow copolymerization, harsh non-selective degradation conditions, and limited application potential because the degradation products (often oligomers or polymers themselves) have properties like the intact species. This work presents fast selective degradation accompanied by a drastic change in a key property, aqueous solubility. The thionolactone dibenzo[c,e]oxepane-5-thione was found to copolymerise radically with a range of primary, secondary, and tertiary neutral and zwitterionic acrylamides with rapid incorporation of degradable biphenyl thiocarboxylate repeat units. Intact copolymers displayed temperature-responsive (LCST or UCST-type) aqueous solubility behaviour, tuneable through the molar composition and (exploiting the non-azeotropic copolymerization behaviour) comonomer sequence. Various conditions led to selective and complete degradation of the backbone thioesters through hydrolysis, aminolysis, transthioesterification (including under physiological conditions), and oxidative hydrolysis which drastically increased aqueous solubility. Polymers containing as little as 8 mol-% of thioester repeat units underwent a temperature-independent insoluble-soluble transition upon degradation with cysteine or potassium persulfate. Insoluble polymers were used to block syringe filters which allowed flow of degradant solutions only, relevant relevant to lab-on-a-chip, sensing, and embolic biomedical applications.
Synthesis and Functionalization of Thiol-Reactive Biodegradable Polymers
Macromolecules, 2012
S Supporting Information I n recent years, reactive degradable polymers have gained increased attention due to their widespread application in biomedical and materials sciences. Recent progress in efficient postfunctionalization strategies of polymeric materials have made such reactive polymers a versatile candidate for the design and synthesis of functional polymeric materials. 1 In particular, biodegradable polymeric materials that can be appropriately functionalized with biologically relevant molecules and biomolecules hold immense promise in the area of the design and fabrication of novel drug delivery systems and tissue engineering. 2 The multivalent nature of polymers allows the attachment of multiple targeting units and drugs, thus increasing the efficacy and payload. Furthermore, the degradability of polymers can be applied advantageously to allow controlled release of the drug over prolonged period of time at the disease site.
Polym. Chem., 2015
We demonstrated herein a kind of thermal and oxidation dual responsive polymer with a novel structure of alternating hydrophilic and hydrophobic segments in the backbone. The polymers were facilely synthesized by thiol-ene polymerization of poly(ethylene glycol) diacrylate (PEGDA) and 1,2-ethanedithiol (EDT) monomers. The resulting PEG-EDT copolymers exhibited a sharp and reversible thermal-induced phase transition in aqueous medium which was identified to be caused by the cooperativity of dehydration of PEG segments and the increased hydrophobic interaction between β-thioether ester segments in the backbone. Additionally, the cloud point temperatures of PEG-EDT copolymers were examined to be dependent on the molecular weight of PEG, polymer concentration, addition of NaCl and isotopic solvent. More importantly, the PEG-EDT copolymers were tested to be oxidation sensitive due to the presence of oxidizable thioether groups in the backbone. The collapsed polymers at elevated temperatures could be easily converted into completely water-soluble polymers by oxidative conversion of hydrophobic thioether groups into hydrophilic sulfoxide and sulfone groups. This oxidation-switchable water solubility inspired us to use this copolymer in design of the oxidation-triggered drug delivery system. Thus, a triblock copolymer mPEG-b-575EDT-b-mPEG was synthesized by a one-pot method. The resulting triblock copolymer could self-assemble into nanoparticles using thermal and oxidation dual responsive 575-EDT as the core and mPEG as the shell. As a consequence, the hydrophobic model drug (i.e., Nile Red) can be effectively encapsulated into the collapsed nanoparticle core at the body temperature while released by oxidation-triggered disruption of the nanoparticles. This tunable thermo-responsive behavior in combination with oxidation-triggerable thioether groups makes these PEG-EDT copolymers promising for reactive oxygen species (ROS) responsive drug delivery. † Electronic supplementary information (ESI) available: The synthesis and characterization of PEGDA1k, additional turbidity measurements, FT-IR spectra, GPC curves, TEM images and fluorescence emission spectra. See
Biomaterials, 2003
A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH) groups was cross-linked in situ to form a polymer hydrogel under mild conditions. No organic solvent, elevated temperature, or harsh pH is required in the formulation or patient administration processes, making it particularly useful for delivery of fragile therapeutics, such as proteins. The in vitro release of fluorescein-labeled bovine serum albumin and the in vivo release of the model proteins, erythropoietin, RANTES and three PEGconjugated RANTES derivatives showed sustained release for 2-4 weeks and demonstrated prolonged biological activity of the released proteins in animals.
Cysteine-Functional Polymers via Thiol-ene Conjugation
Macromolecular Rapid Communications, 2015
as hydroxyl, amino, silane, and others. Unfortunately, cysteines lose their 1,2-aminothiol functionality during thiol-ene chemistry due to the consumption of the thiol group. This vanishes the unique reactivity of 1,2-aminothiols toward thioesters and properties such as redox sensitivity.
Biomacromolecules, 2015
Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degradation. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepared from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-containing diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with average sizes of about 90-120 ...
Biomacromolecules
Fast-forming yet easily dissolvable hydrogels (HGs) have potential applications in wound healing, burn incidences, and delivery of therapeutic agents. Herein, a combination of a thiol− maleimide conjugation and thiol−disulfide exchange reaction is employed to fabricate fast-forming HGs which rapidly dissolve upon exposure to dithiothreitol (DTT), a nontoxic thiol-containing hydrophilic molecule. In particular, maleimide disulfide-terminated telechelic linear poly(ethylene glycol) (PEG) polymer and PEGbased tetrathiol macromonomers are employed as gel precursors, which upon mixing yield HGs within a minute. The selectivity of the thiol−maleimide conjugation in the presence of a disulfide linkage was established through 1 H NMR spectroscopy and Ellman's test. Rapid degradation of HGs in the presence of thiol-containing solution was evident from the reduction in storage modulus. HGs encapsulated with fluorescent dye-labeled dextran polymers and bovine serum albumin were fabricated, and their cargo release was investigated under passive and active conditions upon exposure to DTT. One can envision that the rapid gelation and fast ondemand dissolution under relatively benign conditions would make these polymeric materials attractive for a range of biomedical applications.