Oral mucosal vaccination using integrated fiber microneedles.

The oral mucosa is an attractive site for immunization due to its accessibility and ability to elicit local and systemic immune responses. However, evaluating oral mucosal immunogenicity has proven challenging due to the physical barriers and immunological complexity of the oral mucosa. Microneedles can overcome these physical barriers, but previous work has been limited in the scope of microneedle delivery site, geometry, and release kinetics, all of which are expected to affect physiological responses. Here, we develop integrated fiber microneedle devices, an oral dosage form with tunable geometries and material configurations capable of both burst and sustained release to controlled depths in the oral mucosa. Integrated fiber microneedles administered to either the buccal or sublingual mucosa result in seroconversion and antigen-specific interferon-γ secretion in splenocytes. The dynamics and magnitude of the resulting immune response can be modulated by tuning microneedle release kinetics. Optimal microneedle geometry is site-specific, with longer microneedles eliciting greater immunogenicity in the buccal mucosa, and shorter microneedles eliciting greater immunogenicity in the sublingual mucosa. The Th1/Th2 phenotype of the resulting immune response is also dependent on integrated fiber microneedle length. Together, these results establish integrated fiber microneedles as a multifunctional delivery system for the oral mucosa and motivate further exploration using tunable delivery systems to better understand oral mucosal immunity.

Microneedle-Mediated Vaccine Delivery to the Oral Mucosa.

The oral mucosa is a minimally invasive and immunologically rich site that is underutilized for vaccination due to physiological and immunological barriers. To develop effective oral mucosal vaccines, key questions regarding vaccine residence time, uptake, adjuvant formulation, dose, and delivery location must be answered. However, currently available dosage forms are insufficient to address all these questions. An ideal oral mucosal vaccine delivery system would improve both residence time and epithelial permeation while enabling efficient delivery of physicochemically diverse vaccine formulations. Microneedles have demonstrated these capabilities for dermal vaccine delivery. Additionally, microneedles enable precise control over delivery properties like depth, uniformity, and dosing, making them an ideal tool to study oral mucosal vaccination. Select studies have demonstrated the feasibility of microneedle-mediated oral mucosal vaccination, but they have only begun to explore the broad functionality of microneedles. This review describes the physiological and immunological challenges related to oral mucosal vaccine delivery and provides specific examples of how microneedles can be used to address these challenges. It summarizes and compares the few existing oral mucosal microneedle vaccine studies and offers a perspective for the future of the field.

Sustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery.

Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.