Analytical and Simulation-Based Models for Drug Release and Gel-Degradation in a Tetra-PEG Hydrogel Drug-Delivery System

摘要

We have recently reported drug-releasing, degradable Tetra-PEG hydrogels as a new drug delivery system. The gels contain two self-cleaving beta-eliminative linkers: one that covalently tethers the drug to the gel and releases it at a predictable rate, and another with slower cleavage that is installed in each cross-link of the polymer to control gel degradation. By balancing the two cleavage rates, the system can be designed to discharge most or all of the drug before the gel undergoes significant degradation. If polymer degradation is too rapid, undesirable gel-fragments covalently bound to the drug are released; if too slow, the gel remains in the body as an inert substance for prolonged periods. Here, we describe an analytical theory as well as a Monte Carlo simulation of concurrent drug release from and degradation of Tetra-PEG polymers. Considerations are made for an ideal network as well as networks containing missing bonds and double link defects. The analytical and simulation approaches are in perfect agreement with each other and with experimental data in the regime of interest. Using these models, we are able to (a) compute the time courses of drug release and gel degradation as well as the amount of fragment-drug conjugate present at any time and (b) estimate the rate constants of drug release and gel degradation necessary to control each of the above. We can also account for the size-dependent elimination of gel fragments from a localized semipermeable compartment and hence estimate fragment mass vs time curves in such in vivo compartments. The models described allow design of an optimal Tetra-PEG drug delivery vehicle for a particular use.