Facile Construction of a Two-in-One Injectable Micelleplex-Loaded Thermogel System for the Prolonged Delivery of Plasmid DNA

Abstract

Nanoparticle−hydrogel systems have recently emerged as a class of interesting hybrid materials with immense potential for several biomedical applications. Remarkably, the incorporation of nanoparticles into a hydrogel may yield synergistic benefits lacking in a singular system. However, most synthetic strategies require laborious steps to achieve the system, severely restricting the process of translational research. Herein, a facile strategy to access a two-in-one system comprising two distinct polyurethane (PU)-based micellar systems is demonstrated and applied as a novel sustained gene delivery platform, where the two PUs are synthesized similarly but with slightly different compositions. One PU forms cationic micelles that complex with plasmid DNA (pDNA), which are loaded into a thermogel formed by another PU micellar system for the prolonged release of pDNA micelleplexes. Specifically, a thermogelling multiblock PU copolymer (denoted as EPH) was synthesized via the step-growth polymerization of poly(ethylene glycol), poly(propylene glycol), and poly(3-hydroxybutyrate). By further introducing a cationic extender, 3-(dimethylamino)-1,2propanediol, into the reaction feed, a series of cationic PUs (denoted as EPHD) with varying compositions were obtained. The EPHDs formed positively charged micelles in aqueous solutions, efficiently condensed pDNA into nano-sized micelleplexes (<200 nm) at optimized w/w ratios, and mediated transient green fluorescence protein expression in HEK293T cells at 48 h posttransfection. On the other hand, aqueous EPH solution (4 wt %) was injectable at 4 °C and rapidly gelled upon heating to 37 °C to form a stable hydrogel depot. EPHD/pDNA micelleplexes were easily loaded into EPH by mixing the solutions at 4 °C, before heating to 37 °C, leading to the resultant hydrogel system. The in vitro release study revealed that while free pDNA loaded in the thermogel was completely released in 2 weeks, the release of EPHD/pDNA micelleplexes was prolonged to at least 28 days, suggesting substantial micelleplex−hydrogel interactions. Intact, bioactive, and noncytotoxic EPHD/pDNA micelleplexes in the release media were proved by gel retardation, in vitro gene transfection, and CCK-8 cytotoxicity assay results, respectively. Collectively, this work presents a simple approach to achieving and optimizing a novel two-in-one nanoparticle−hydrogel system for the prolonged delivery of pDNA and may be promising for long-term gene delivery applications.

Codelivery of Doxorubicin and p53 Gene by β-Cyclodextrin-Based Supramolecular Nanoparticles Formed via Host–Guest Complexation and Electrostatic Interaction

“…Furthermore, CDs have low cytotoxicity and good bioavailability; hence, they are suitable for use in drug delivery systems . Among CDs, β-CD has been widely used for pharmaceutical applications due to its ease of availability and appropriate cavity size for a variety of hydrophobic drugs and guest molecules. − For example, Dox was loaded onto β-CD-functionalized quantum dots and delivered to multidrug-resistant HeLa cells to overcome multidrug resistance . Fluorouracil (5-FU), an anticancer drug, was encapsulated by cationic β-CD at a high encapsulation efficiency of 80%, demonstrating that β-CD could serve as a good drug carrier for drug delivery .…”

Cationic micelles as nanocarriers for enhancing intra-cartilage drug penetration and retention

“…14 Among the drug carriers, polymeric micelles have emerged as attractive nanocarriers for drug delivery due to their advantages, such as nanosize, easy cell internalization, simple functionalization, increased bioavailability of hydrophobic drugs, physical encapsulation without drug modification, and flexibility. [15][16][17][18][19][20] To our knowledge, there are few studies that investigate the feasibility and effectiveness of cationic micelles in intra-cartilage drug delivery.…”

Enhancing the Gene Transfection of Poly(β-amino ester)/DNA Polyplexes by Modular Manipulation of Amphiphilicity

“…Inspired by the modular strategy applied in Li et al’s studies that optimized the siRNA delivery through the host–guest chemistry modularization between a β-cyclodextrin–based cationic host polymer and a guest polymer functionalized by the adamantyl group and prolonged the delivery of pDNA through two-in-one modularization of two distinct polyurethane-based micellar systems. , Meanwhile, consider that amphiphilic polymers condense nucleic acids into polyplexes, whose amphiphilicity results from the hydrophobic components and the hydrophilic components of the polymers. It can be envisioned that if a hydrophobic polymer and a hydrophilic polymer are synthesized separately and used as a hydrophobic module and a hydrophilic module, respectively, the amphiphilicity of the polyplexes can be modulated by incorporating different proportions of the two modules.…”