Ordered and Kinetically Discrete Sequential Protein Release from Biodegradable Thin Films

Abstract

Multidrug regimens can sometimes treat recalcitrant diseases when single-drug therapies fail. Recapitulating complex multidrug administration from controlled release films for localized delivery remains challenging because their release kinetics are frequently intertwined and an initial burst release of each drug is usually uncontrollable. Herein we demonstrate kinetic control over protein release by crosslinking Layer-by-Layer films during the assembly process.

Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper–Hollow Silica Nanoparticles

“…The primary strategy to overcome MDR is co-administration of multiple drugs789. However, varying drug uptake and suboptimal drug concentrations in heterogeneous tumour environments limit the synergistic efficacy of administered drugs101112.…”

“…Multidrug resistance (MDR) of cancer has been responsible for the high recurrence rate and failure of cancer chemotherapy; more than 90% of patients die due, to a certain extent, to MDR 1 2 3 4 5 6 . The primary strategy to overcome MDR is co-administration of multiple drugs 7 8 9 . However, varying drug uptake and suboptimal drug concentrations in heterogeneous tumour environments limit the synergistic efficacy of administered drugs 10 11 12 .…”

Scaffold-mediated sequential drug/gene delivery to promote nerve regeneration and remyelination following traumatic nerve injuries

“…One approach to control the degradation rate of DDS with the aim to achieve sequential drug release is through altering the degree of material crosslinking [198,230,270]. Increase in crosslinking density increases the resistance of material to hydrolysis and thus, decreases the material degradation time and ultimately the drug release kinetics [271].…”

Layer‐by‐layer approaches to staging medicine from surfaces

“…By incorporating known biologically compatible quantitative click chemistries, we have been able to demonstrate the formation of in situ crosslinks with direct adsorption from aqueous solutions . For improved biocompatibility and bioorthogonality, we most recently investigated the use of the poly(β‐ l ‐malic acid) (PMLA) backbone, which is a negatively charged polyanion that undergoes hydrolysis along its ester backbone and contains a carboxylic side group that can be used as a handle for functionalization and a source of high charge density .…”

“…We assembled films composed of an alternating tetralayer of (chitosan/PMLA‐az/lysozyme/PMLA‐DBCO) n that underwent crosslinking during the construction of the film. We found that the inclusion of these covalent crosslinks during film assembly limited the interdiffusion that causes the mixing of components . It was possible to effectively partition the model protein, lysozyme, within a defined compartmental region; this resulted in the complete delay of release of the highly interdiffusive protein for 24 h. The length of time of drug delay depended on the number of layers introduced.…”