Cameron Ball

Two-dimensional paper networks

Most laboratory assays take advantage of multi-step protocols to achieve high performance, but conventional paper-based tests (e.g., lateral flow tests) are generally limited to assays that can be carried out in a single fluidic step. We have developed two-dimensional paper networks (2DPNs) that use materials from lateral flow tests but reconfigure them to enable programming of multi-step reagent delivery sequences. The 2DPN uses multiple converging fluid inlets to control the arrival time of each fluid to a detection zone or reaction zone, and it requires a method to disconnect each fluid source in a corresponding timed sequence. Here, we present a method that allows programmed disconnection of fluid sources required for multi-step delivery. A 2DPN with legs of different lengths is inserted into a shared buffer well, and the dropping fluid surface disconnects each leg at in a programmable sequence. This approach could enable multi-step laboratory assays to be converted into simple point-of-care devices that have high performance yet remain easy to use.

Drug-Eluting Fibers for HIV-1 Inhibition and Contraception

Multipurpose prevention technologies (MPTs) that simultaneously prevent sexually transmitted infections (STIs) and unintended pregnancy are a global health priority. Combining chemical and physical barriers offers the greatest potential to design effective MPTs, but integrating both functional modalities into a single device has been challenging. Here we show that drug-eluting fiber meshes designed for topical drug delivery can function as a combination chemical and physical barrier MPT. Using FDA-approved polymers, we fabricated nanofiber meshes with tunable fiber size and controlled degradation kinetics that facilitate simultaneous release of multiple agents against HIV-1, HSV-2, and sperm. We observed that drug-loaded meshes inhibited HIV-1 infection in vitro and physically obstructed sperm penetration. Furthermore, we report on a previously unknown activity of glycerol monolaurate (GML) to potently inhibit sperm motility and viability. The application of drug-eluting nanofibers for HIV-1 prevention and sperm inhibition may serve as an innovative platform technology for drug delivery to the lower female reproductive tract.

Drug Synergy of Tenofovir and Nanoparticle-Based Antiretrovirals for HIV Prophylaxis

Background The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV). Methodology/Principal Findings Biodegradable poly(lactide-co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ∼200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1∶50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1∶1 ratio of IC50 values. TFV combined with NP-SQV at a 1∶1 ratio of IC50 values also showed strong synergy (CI50 = 0.07). Conclusions ARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities.

Electrospun Solid Dispersions of Maraviroc for Rapid Intravaginal Preexposure Prophylaxis of HIV

ABSTRACT The development of topical anti-human immunodeficiency virus (HIV) microbicides may provide women with strategies to protect themselves against sexual HIV transmission. Pericoital drug delivery systems intended for use immediately before sex, such as microbicide gels, must deliver high drug doses for maximal effectiveness. The goal of achieving a high antiretroviral dose is complicated by the need to simultaneously retain the dose and quickly release drug compounds into the tissue. For drugs with limited solubility in vaginal gels, increasing the gel volume to increase the dose can result in leakage. While solid dosage forms like films and tablets increase retention, they often require more than 15 min to fully dissolve, potentially increasing the risk of inducing epithelial abrasions during sex. Here, we demonstrate that water-soluble electrospun fibers, with their high surface area-to-volume ratio and ability to disperse antiretrovirals, can serve as an alternative solid dosage form for microbicides requiring both high drug loading and rapid hydration. We formulated maraviroc at up to 28 wt% into electrospun solid dispersions made from either polyvinylpyrrolidone or poly(ethylene oxide) nanofibers or microfibers and investigated the role of drug loading, distribution, and crystallinity in determining drug release rates into aqueous media. We show here that water-soluble electrospun materials can rapidly release maraviroc upon contact with moisture and that drug delivery is faster (less than 6 min under sink conditions) when maraviroc is electrospun in polyvinylpyrrolidone fibers containing an excipient wetting agent. These materials offer an alternative dosage form to current pericoital microbicides.

Coaxially electrospun fiber-based microbicides facilitate broadly tunable release of maraviroc.

Electrospun fibers show potential as a topical delivery system for vaginal microbicides. Previous reports have demonstrated delivery of anti-HIV and anti-STI (sexually transmitted infection) agents from fibers formulated using hydrophilic, hydrophobic, or pH-responsive polymers that result in rapid, prolonged, or stimuli-responsive release, respectively. However, coaxial electrospun fibers have yet to be evaluated as a highly tunable microbicide delivery vehicle. In this research, we explored the opportunities and limitations of a model coaxial electrospun fiber system to provide broad and tunable release rates for the HIV entry inhibitor maraviroc. Specifically, we prepared ethyl cellulose (EC)-shell and polyvinylpyrrolidone (PVP)-core fibers that were capable of releasing actives over a range of hours to several days. We further demonstrated simple and effective methods for combining core-shell fibers with rapid-release formulations to provide combined instantaneous and sustained maraviroc release. In addition, we investigated the effect of varying release media on maraviroc release from core-shell fibers, and found that release was strongly influenced by media surface tension and drug ionization. Finally, in vitro cell culture studies show that our fiber formulations were not cytotoxic and that electrospun maraviroc maintained similar antiviral activity compared to neat maraviroc.