Dissolving microneedle array patches containing mesoporous silica nanoparticles of different pore sizes as a tunable sustained release platform

Abstract

Dissolving microneedle array patches (DMAPs) enable efficient and painless delivery of therapeutic molecules across the stratum corneum and into the upper layers of the skin. Furthermore, this delivery strategy can be combined with the sustained release of nanoparticles to enhance the therapeutic potential in a wide variety of pathological scenarios. Among the different types of nanoparticles that can be included in microneedle formulations, mesoporous silica nanoparticles (MSNs) of tuneable pore sizes constitute a promising tool as drug delivery systems for cargos of a wide range of molecular weights. However, the development of efficient methods to produce DMAP containing large amounts of MSNs of different pore sizes has not been reported. In this work, DMAP containing MSNs with varying pore sizes was prepared and characterized. After synthesizing and characterizing MSNs, the pore size of the nanoparticles (in the range of 3 to 13 nm for S-MSN and XL-MSN, respectively) was observed to influence the loading and release of both small and large molecules, using fluorescein and ovalbumin (OVA) as model cargos. Moreover, a new preparation method was developed to produce DMAP containing large amounts of these MSNs located mainly in the microneedle tips. The successful insertion of these DMAPs was confirmed in vitro (using Parafilm), ex vivo (using excised neonatal porcine skin) and in vivo (in the back of mice) models. The dissolution of the microneedles and deposition of the nanoparticles inside the skin were also confirmed both ex vivo and in vivo using fluorescent nanoparticles, with complete microneedle dissolution after 2 h of insertion in vivo. Through histological studies, the microneedle-delivered MSNs were found to end up inside antigen presenting cells in the skin tissue (either F4/80+ macrophages or CD11c+ dendritic cells). For this reason, the uptake and biological effect of the MSNs was evaluated in vitro in dendritic cells, showing that while smaller pore MSNs were taken up by cells more efficiently (with over 80 % of S-MSN uptake compared to ca. 55 % for XL-MSNs), the dendritic cells treated with OVA- loaded XL-MSNs underwent the largest degree of activation (inducing over 25 % of CD40 expression compared to less than 2 % for OVA-loaded S- MSNs). Finally, the immune response to OVA-loaded XL-MSNs in mice was evaluated after repeated administration either subcutaneously or through DMAP. The results of this experiment showed comparable levels of anti-ovalbumin immunoglobulin generation through both routes of administration (with significant production of OVA-specific IgG1 and IgG2b antibodies), highlighting the good potential of this delivery platform for vaccination or immunotherapy applications.