Surface Eroding, Semicrystalline Polyanhydrides via Thiol–Ene “Click” Photopolymerization

Abstract

Surface eroding and semicrystalline polyanhydrides, with tunable erosion times and drug delivery pharmacokinetics largely dictated by erosion, are produced easily with thiol-ene "click" polymerization. This strategy yields both linear and cross-linked network polyanhydrides that are readily and fully cured within minutes using photoinitiation, can contain up to 60% crystallinity, and have tensile moduli up to 25 MPa for the compositions studied. Since they readily undergo hydrolysis and exhibit the oft-preferred surface erosion mechanism, they may be particularly useful in drug delivery applications. The polyanhydrides were degraded under pseudophysiological conditions and cylindrical samples (10 mm diameter × 5 mm height) were completely degraded within ∼10 days, with the mass-time profile being linear for much of this time after a ∼24 h induction period. Drug release studies, using lidocaine as a model, showed pharmacokinetics that displayed a muted burst release in the early stages of erosion, but then a delayed release profile that is closely correlated to the erosion kinetics. Furthermore, cytotoxicity studies of the linear and cross-linked semicrystalline polyanhydrides, and degradation products, against fibroblast cells indicate that the materials have good cytocompatibility. Overall, cells treated with up to 2500 mg/L of the semicrystalline polyanhydrides and degradation products show >90% human dermal fibroblast adult (HDFa) cell viability indicative of good cytocompatibility.

Quantitative and qualitative toxicological evaluation of thiol-ene “click” chemistry-based polyanhydrides and their degradation products

“…However, most of these PAH materials are typically synthesized under relatively harsh reaction conditions via polycondensation reactions, which may involve high heat, vacuum and potentially tedious monomer synthesis . More recently, we have developed a relatively mild and facile method for making photocurable PAHs, which may be linear or cross‐linked, using thiol‐ene “click” reactions (Scheme ). These materials are moldable and can be easily adapted for localized delivery of drugs, have recently been demonstrated to perform as reconfigurable shape memory polymer composites and can be formulated into nanoparticles .…”

“…More recently, we have developed a relatively mild and facile method for making photocurable PAHs, which may be linear or cross‐linked, using thiol‐ene “click” reactions (Scheme ). These materials are moldable and can be easily adapted for localized delivery of drugs, have recently been demonstrated to perform as reconfigurable shape memory polymer composites and can be formulated into nanoparticles . However, for polymeric delivery applications, the polymeric vehicles are required to meet stringent toxicity and biocompatibility requirements before they can be seriously considered for use in therapeutic applications.…”

“…However, for polymeric delivery applications, the polymeric vehicles are required to meet stringent toxicity and biocompatibility requirements before they can be seriously considered for use in therapeutic applications. In our previous articles, we performed some preliminary toxicity experiments on both amorphous and semicrystalline thiol‐ene based PAH materials, and although both polymer types appear to have low toxicity levels, the tests used were limited; for example, no MTT assay or proliferation studies were done on the amorphous PAH. Thus, it is necessary to assess the toxicity of these materials more completely.…”

Polyanhydride nanoparticles by ‘click’ thiol–ene polymerization

“…6,7 Anhydrides are another well-known hydrolytically unstable moiety, yet are not anywhere near as commonly used in degradable polymers as esters in part because of the faster hydrolysis rates of anhydrides that may make them more difficult to work with and limits their shelf life. [9][10][11][12] As part of the 'click' chemistry toolbox, these reactions can be initiated via photo, thermal, or redox means, are rapid and high yielding, and can provide easy post-polymerization functionalization. We improved this situation greatly by showing that polyanhydrides can simply and effectively be synthesized using thiol-ene 'click' polymerizations.…”

The composition of polyanhydrides used in particle-based cancer vaccines affects the magnitude of the antitumor immune response

“…Some biodegradable polymers are hydrophilic, such as PLGA, and degrade via bulk erosion[36]. In contrast, hydrophobic biodegradable polymers, such as polyanhydrides, degrade via surface erosion[37].Polyanhydrides are synthetic biodegradable polymers composed of repeated units of backbone monomers which are linked by anhydride bonds. Polyanhydride copolymers are commonly synthesized from diacid (dicarboxylic acid) monomers by melt polycondensation.…”