Designing Polyelectrolyte Microneedles Based on Borylated Poly(β-aminoester) Polymers To Enhance Transdermal pH-Controlled Delivery of Nucleic Acids

Abstract

The use of transdermal delivery for nucleic acidadministration is an interesting approach to overcoming limitations ofsystemic administration routes, such as first-pass effects, the painfulneedle injection, or their poor biodistribution. Thus, the use of amicroneedle-based patch could represent a turning point for nucleic aciddelivery, thanks to the possibility of self-administration of the actives in apainless and easy procedure. However, the design of transdermal systemswith a higher degree of precision release is a clear need that has not beenfully resolved. Committed to tackling this challenge, we present here amicroneedle patch that involves a smart delivery system supported by thewell-established ability of boronic acid to interact with carbohydrates in apH-dependent manner. This system builds up a multilayer structure overa solid microneedle platform whose surface has been modified toimmobilize glucosamine units that are able to interact with anoligopeptide-end terminated poly(β-aminoester) that presents a 4-carboxy-3-fluorophenylboronic acid (Bor-pBAE). Thus,sequential layers of the Bor-pBAE and plasmid DNA have been assembled, thanks to the ability of the polymer to interact withthe nucleic acid at a basic pH and then gradually release the plasmid under two different conditions of pH (the physiological pH =7.4 and the acidic pH = 5.1). We set up the design and implementation of this first proof of concept while demonstratingmicroneedles' safety and functionality. Additionally, we have shown the efficacy of the construct to express the encoded genes inmodel cell lines. In conclusion, we have established the basis to confirm that this generation of borylated poly(β-aminoesters) holdsgreat promise as a transdermal local nucleic acid delivery system.