The ability to deliver but hide immunogenic payloads and then reveal them at predetermined times could lead to autonomously boosting vaccine formulations or improved antigen–adjuvant vaccine designs. We used in silico modeling to determine the appropriate formulation and material properties for poly(lactic-co-glycolic) acid (PLGA) microparticles such that they would delay the in vitro “unmasking” of an ovalbumin-alum payload for precise and predetermined intervals. A preferred formulation was then tested in vivo. In vivo T cell proliferation data confirmed the presentation of antigen released through the programmed delayed burst while antibody subclass data demonstrated immunogenicity comparable to that observed with established multiple injection prime-boost regimens.
Journal of Materials Chemistry B, 2014
S. N. Rothstein, C. Donahue, L. D. Falob, and S. R. Little
Although approved by the U.S. Food and Drug Administration, enfuvirtide is rarely used in combination antiretroviral therapies (cART) to treat HIV-1 infection, primarily because of its intense dosing schedule that requires twice-daily subcutaneous injec- tion. Here, we describe the development of enfuvirtide-loaded, degradable poly(lactic-co-glycolic) acid microparticles that provide linear in vitro release of the drug over an 18-day period. This sustained-release formulation could make enfuvirtide more attractive for use in cART.
Antimicrobial Agents and Chemotherapy, 2014
Sam N. Rothstein, Kelly D. Huber, Nicolas Sluis-Cremer, Steven R. Little
A unified model has been developed to predict release not only from bulk eroding and surface eroding systems but also from matrices that transition from surface eroding to bulk eroding behavior during the course of degradation. This broad applicability is afforded by fundamental diffusion/reaction equations that can describe a wide variety of scenarios including hydration of and mass loss from a hydrolysable polymer matrix. Together, these equations naturally account for spatial distributions of polymer degradation rate. In this model paradigm, the theoretical minimal size required for a matrix to exhibit degradation under surface eroding conditions was calculated for various polymer types and then verified by empirical data from the literature. An additional set of equations accounts for dissolution- and/or degradation-based release, which are dependent upon hydration of the matrix and erosion of the polymer. To test the model’s accuracy, predictions for agent egress were compared to experimental data from polyanhydride and polyorthoester implants that were postulated to undergo either dissolution-limited or degradation-controlled release. Because these predictions are calculated solely from readily attainable design parameters, it seems likely that this model could be used to guide the design controlled release formulations that produce a broad array of custom release profiles.
Biomaterials 30 (2009)
Sam N. Rothsteina, William J. Federspiel, Steven R. Little
DOI:10.1016/j.biomaterials.20 08.12.0 02
Controlled release technology could provide a universal solution to the problems of patient compliance and sub-optimal dosing that often plague modern pharmaceuticals. Yet, harnessing this potential requires the ability to design drug delivery formulations which satisfy specific dosing schedules. This review intends to portray how material properties, processing methods and mathematical models can serve as effective tools for rationally tuning the duration and rate of drug release from biodegradable polymer matrices.
J. Mater. Chem., 2011, 21, 29–39
Sam N. Rothstein and Steven R. Little
A broadly applicable model for predicting controlled release could eliminate the need for exploratory, in vitro experiments during the design of new biodegradable matrix-based therapeutics. We have developed a simple mathematical model that can predict the release of many different types of agents from bulk eroding polymer matrices without regression. New methods for deterministically calculating the magnitude of the initial burst and the duration of the lag phase (time before Fickian release) were developed to enable the model’s broad applicability. To complete the model’s development, such that predictions can be made from easily measured or commonly known parameters, two correlations were developed by fitting the fundamental equations to published controlled release data. To test the model, predictions were made for several different biodegradable matrix systems. In addition, varying the readily attainable parameters over rational bounds shows that the model predicts a wide range of therapeutically relevant release behaviors.
Journal of Materials Chemistry, 2008, 18, 1873–1880
Sam N. Rothstein, William J. Federspiel, Steven R. Little