Multiresponsive Nanogels for the Selective Delivery of Antimicrobial Drugs to Mucosal Tissues.

Effective drug delivery to bacterially infected mucosa remains a challenge due to the combined obstacles of the mucosal barrier, pH variations, and high concentrations of glutathione. However, polysaccharide-based responsive nanogels (NGs) can take advantage of these conditions to deliver specific antimicrobials. We explored the critical features of pH- and redox-responsive NGs to increase drug penetration, residence time, and efficacy in the infected mucosa. We prepared multifunctional NGs using hydroxypropyl cellulose as a template for the cross-linking of methacrylic acid with N,N'-bis(acryloyl)cystamine (BAC) or N,N'-methylenebis(acrylamide) (BIS). Studies of NG-mucin binding and the antibacterial efficacy of doxycycline-loaded NGs revealed the interplay between the response to pH and redox clues. Specifically, higher BAC composition increased mucus binding and controlled release in reductive conditions, while higher BIS composition yielded NGs with higher doxycycline-mediated antibacterial efficacy against Staphylococcus aureus. The findings reveal the potential of multiresponsive NGs in effective antimicrobial delivery in infected mucosa.

Unveiling the Potential of Surface Polymerized Drug Nanocrystals in Targeted Delivery.

Nanocrystals (NCs) have entirely changed the panorama of hydrophobic drug delivery, showing improved biopharmaceutical performance through multiple administration routes. NCs are potential highly loaded nanovectors due to their pure drug composition, standing out from conventional polymers and lipid nanoparticles that have limited drug-loading capacity. However, research in this area is limited. This study introduces the concept of surface modification of drug NCs through single-layer poly(ethylene glycol) (PEG) polymerization as an innovative strategy to boost targeting efficiency. The postpolymerization analysis revealed size and composition alterations, indicating successful surface engineering of NCs of the model drug curcumin of approximately 200 nm. Interestingly, mucosal tissue penetration analysis showed enhanced entry for fully coated and low cross-linked (LCS) PEG NCs, with an increase of 15 µg/cm2 compared to the control NCs. In addition, we found that polymer chemistry variations on the NCs' surface notably impacted mucin binding, with those armored with LCS PEG showing the most significant reduction in interaction with this glycoprotein. We validated this strategy in an in vitro nose-to-brain model, with all of the NCs exhibiting a promising ability to cross a tight monolayer. Furthermore, the metabolic and pro-inflammatory activity revealed clear indications that, despite surface modifications, the efficacy of curcumin remains unaffected. These findings highlight the potential of surface PEGylated NCs in targeted drug delivery. Altogether, this work sets the baseline for further exploration and optimization of surface polymerized NCs for enhanced drug delivery applications, promising more efficient treatments for specific disorders and conditions requiring active targeting.

Leveraging novel innovative thermoresponsive polymers in microneedles for targeted intradermal deposition.

Microneedles have garnered considerable attention over the years as a versatile pharmaceutical platform that could be leveraged to deliver drugs into and across the skin. In the current work, poly (N-isopropylacrylamide) (PNIPAm) is synthesized and characterized as a novel material for the development of a physiologically responsive microneedle-based drug delivery system. Typically, this polymer transitions reversibly between a swell state at lower temperatures and a more hydrophobic state at higher temperatures, enabling precise drug release. This study demonstrates that dissolving microneedles patches made from PNIPAm, incorporating BIS-PNIPAm, a crosslinked polymer variant, exhibit enhanced mechanical properties, evident from a smaller height reduction in microneedle (∼10 %). Although microneedles using PNIPAm alone were achievable, it displayed poor mechanical strength, requiring the inclusion of additional polymeric excipients like PVA to enhance mechanical properties. In addition, the incorporation of a thermoresponsive polymer did not have a significant (p > 0.05) impact on the insertion properties of the needles as all formulations inserted to a similar depth of 500 µm into ex vivo skin. Furthering this, the needles were loaded with a model payload, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DID) and the deposition of the cargo was monitored via multiphoton microscopy that showed that a deposit is formed at a depth of ≈200 µm. Also, it was revealed that crosslinked-PNIPAm (Bis-PNIPAm) formulations exhibited notable skin accumulationof the dye only after 4 h, independent of the excipient matrix used. This phenomenon was absent in non-crosslinked PNIPAm formulations, indicating a deposit formation in Bis-PNIPAm microneedle formulation. Collectively, this proof-of-concept study has advanced our understanding on the possibility to use PNIPAm for dissolving microneedle fabrication which could be harnessed for the deposition of nanoparticles into the dermis, for extended drug release within the skin.