Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes

Abstract

Direct pulmonary delivery is a promising step in developing effective gene therapies for respiratory disease. Gene therapies can be used to treat the root cause of diseases, rather than just the symptoms. However, developing effective therapies that do not cause toxicity and that successfully reach the target site at therapeutic levels is challenging. We have developed a polymer-DNA complex utilizing polyethylene imine (PEI) and DNA, which was then encapsulated into poly(lactic acid)-co-monomethoxy poly(ethylene glycol) (PLA-mPEG) microparticles via double emulsion, solvent evaporation. Then, the resultant particle size, porosity, and encapsulation efficiency were measured as a function of altering preparation parameters. Microsphere formation was confirmed from scanning electron micrographs and the aerodynamic particle diameter was measured using an aerodynamic particle sizer. Several formulations produced particles with aerodynamic diameters in the 0-5 μm range despite having larger particle diameters which is indicative of porous particles. Furthermore, these aerodynamic diameters correspond to high deposition within the airways when inhaled and the measured DNA content indicated high encapsulation efficiency. Thus, this formulation provides promise for developing inhalable gene therapies.

Biocompatibility, biodegradation and biomedical applications of poly(lactic acid)/poly(lactic-co-glycolic acid) micro and nanoparticles

“…Moreover, these delivery systems have been tested with great results for pulmonary administration of different drugs (Feng et al 2014;Gaspar et al 2019;Takami and Murakami 2011). Furthermore, therapeutic gene delivery based on these systems has been explored especially loading pDNA, mRNA, siRNA and microRNA (Gomes dos Reis et al 2019;Matta and Maalouf 2019;Nishio et al 2018;Terry et al 2019;Xu et al 2018;Zhao et al 2018).…”

Encapsulating Polyethyleneimine-DNA Nanoplexes into PEGylated Biodegradable Microparticles Increases Transgene Expression In Vitro and Reduces Inflammatory Responses In Vivo

“…The PLA-PEG co-polymers used in this study have been previously described (23). PLGA monomers of D,L-lactide/ glycolide at a 50:50 molar ratio and inherent viscosity of 0.47 dL/g were purchased from Absorbable Polymers International (Pelham, AL).…”

“…Several parameters can help with reducing this xenobiotic response within the lung, including tailoring the size and/ or composition of the microparticles. Particle size may be tailored by changing the overall diameter of spherical particles, the morphology of particles, or by varying the porosity of particles which changes the effective diameter, also known as the aerodynamic diameter (23,24). The polymeric composition may be altered by including copolymers, notably by using poly(ethylene glycol) (PEG).…”

3D Printing in Drug Delivery Systems

“…Our group has been extensively working on drug delivery systems that span from controlled drug release nanoparticles [13,14] to pulsatile drug release PDMS chips [15] and scaffolds [4]. Nanoparticles made from natural and synthetic biocompatible polymers were investigated for their ability to deliver chemotherapeutic drugs [13], gene-activated plasmids [16] and antigens as vaccines [17]. Three-dimensional printing of tablets has demonstrated its potential for controlled drug release [4].…”