Microneedle-array patches loaded with dual mineralized protein/peptide particles for type 2 diabetes therapy

Abstract

The delivery of therapeutic peptides for diabetes therapy is compromised by short half-lives of drugs with the consequent need for multiple daily injections that reduce patient compliance and increase treatment cost. In this study, we demonstrate a smart exendin-4 (Ex4) delivery device based on microneedle (MN)-array patches integrated with dual mineralized particles separately containing Ex4 and glucose oxidase (GOx). The dual mineralized particle-based system can specifically release Ex4 while immobilizing GOx as a result of the differential response to the microenvironment induced by biological stimuli. In this manner, the system enables glucose-responsive and closed-loop release to significantly improve Ex4 therapeutic performance. Moreover, integration of mineralized particles can enhance the mechanical strength of alginate-based MN by crosslinking to facilitate skin penetration, thus supporting painless and non-invasive transdermal administration. We believe this smart glucose-responsive Ex4 delivery holds great promise for type 2 diabetes therapy by providing safe, long-term, and on-demand Ex4 therapy.

Microneedle‐Array Patch Fabricated with Enzyme‐Free Polymeric Components Capable of On‐Demand Insulin Delivery

“…To this end, SF plays a primary role in increasing the stiffness of our hybrid MN‐array patch, which is also a function of monomer concentration and crosslinking density of the semi‐IPN hydrogel (Table S2, Supporting Information). The mechanical strength of the MN‐array patch fabricated with a monomer concentration of 0.6 m and 20% crosslinking density was 0.738 ± 0.112 N per needle ( Figure A), which provided a 12.3‐fold margin of safety over the force required for insertion into the skin (0.06 N per needle) without breaking (Figure B), remarkably stronger than the majority of the hydrogel‐forming MNs reported to date . The hybrid MN‐array patch was able to effectively penetrate mouse and porcine skin, as evidenced by microchannels formed on the skin, based on trypan blue staining (Figure C) and SEM imaging (Figure D).…”

“…In summary, we developed an “enzyme‐free” polymeric MN‐array patch composed of a boronate‐gel/SF semi‐IPN hydrogel, which can provide on‐demand and automated insulin delivery with an aqueous stability of at least 2 months and a sustained performance durability. Achieving both (at once) fast and long‐lasting glucose‐responsiveness has been a challenge with currently available chemically controlled closed‐loop systems . Note that all reported GO x ‐nanoparticle‐based insulin‐loaded MNs suffer from a short duration of action (typically on the order of several hours even for small animals), due to their burst‐responsive and transient (irreversible particle disassociation) natures .…”

“…On one hand, these approaches offer a potentially attractive solution to improve patients' quality of life (QoL), one of the unmet medical needs in the treatment of diabetes, while on the other hand, the use of GO x causes some severe concerns. Alongside intolerance of long‐term use and storage due to issues with protein denaturation, clearance or blockade of toxic byproduct hydrogen peroxide and GO x itself remains a challenge . Another disadvantage inherent to such nanoparticle‐based formulations is the fact that their “burst‐like” response generally lacks the ability to facilitate sustained release, typically resulting in only hourly scale duration, and release profiles that are rate determined by the erosion mode …”

Polymeric microneedles for transdermal protein delivery

“…Effective delivery of proteins with enzymatic or regulatory activity has been developed using MN technology, including insulin, desmopressin, erythropoietin, lysozyme, glucagon, glucagon-like peptide-1 (GLP-1), parathyroid hormone (PTH), growth hormone and etanercept [6,42,63]. The selections of materials and formulation to preserve the protein drug stability remain to be a challenge, particularly in large-scale storage schemes and in production chains for clinical use.…”

“…Using diabetic C57BL/6 db/db mice as a model, they demonstrated the crosslinked alginate patch loaded with 300 μg Ex4 could control the BG of mice for 5 to 6 days. Furthermore, by integrating the mineralized particles, the failure force of the needles was significantly increased to facilitate skin penetration [63]. …”