Characterization and Optimization of PLA Stereocomplexed Hydrogels for Local Gene Delivery Systems

Abstract

Localized gene delivery still remains as a challenging therapeutic method due to the multiple hurdles to overcome. One of the significant factors is a development of a matrix to carry and safely deliver genes at the local site in a controlled manner and then exit and disintegrate harmlessly. This report describes the structural and mechanistic studies on the in-situ forming hydrogels composed of the PEI/DNA multi-layered micelles to apply for gene therapy. The stereocomplexation-driven hydrogel systems from the DNA-loaded and DNA-free PLA-PEG-PLA triblock copolymer micelles that include enantiomeric polylactide blocks exhibited a sol-to-gel transitions between room and body temperatures. These hydrogels have well-described structure and compositions, and improved mechanical properties. Furthermore, the investigation of their degradation profiles and chemical analysis indicated the faster acidic degradation and stepwise degradation process of these micelle–hydrogel systems.

Polymer-Based Systems for Controlled Release and Targeting of Drugs

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The current need to find new advanced approaches to carry biologically active substances (conventional organic drugs, peptides, proteins (such as antibodies), and nucleic acid-based drugs (NABDs such as siRNA and miRNA)) in the body fluids, to realize targeted therapies and even personalized ones, goes hand in hand with research on the performance of new materials to better realize appropriate drug vectors [1].Polymeric materials can be designed and manufactured to obtain delivery systems with the appropriate characteristics in terms of drug release and performance [2]. For use in human applications, the polymer must primarily be biocompatible and non-toxic, and then functionalizable to give the appropriate structural and functional characteristics, such as to make it easily workable, processed, and engineered to obtain the desired system, and to be applied in drug delivery and targeting and/or in diagnosis of diseases.The further possibility of decorating the surface of these polymeric systems (due to the characteristics of the material that constitutes the matrix) with ligands capable of interacting specifically with membrane receptors on cells represents a unique advantage for obtaining targeted drug release to a specific organ, tissue, or cell type [3][4][5][6][7].In this issue, some current examples of design and production of polymeric materials, as well as of searching strategies to modify existing ones, for the making of innovative systems for drug delivery and/or regenerative medicine are collected.In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17].

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“…All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17]. The starting polymeric materials were chosen from hydrophilic polysaccharides [11,16] to hydrophobic polyesters [9,14], obtaining blended materials or copolymers, which were used to obtain drug delivery systems by using techniques such as microfluidics or hot punching [12,13].Polymeric porous microparticles are currently emerging due to their potential for various applications, such as floating drug delivery systems and inhaled formulations. Amoyav and coworkers described the preparation of porous microspheres (MPs) starting from poly(lactic-co-glycolic) acid (PLGA) and poly(d,l-lactide) (PLA), with varying sizes and morphologies, by a simple flow-focusing microfluidic device [13].Characterization of obtained systems to predict the in vivo fate is a fundamental aspect for researchers.…”

“…In particular, polymeric systems from nanoscale (micelles [8,9], nanoparticles [10,11]) to microscale structures (microparticles [12,13]), and to macrodevices (hydrogels [14] and films [15]) were produced. All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17].…”

“…All the described systems were designed for the controlled and targeted release of conventional or biological drugs, such as paclitaxel [10], or siRNA [11] in the treatment of diseases such as cancer [8] and buccal and skin infections [15,16] by the systemic or local administration route [17]. The starting polymeric materials were chosen from hydrophilic polysaccharides [11,16] to hydrophobic polyesters [9,14], obtaining blended materials or copolymers, which were used to obtain drug delivery systems by using techniques such as microfluidics or hot punching [12,13].…”

“…In particular, siRNA-loaded magnetoplexes were able to release siRNA in a redox-triggered manner due to intracellular glutathione (GSH) mediated reduction of disulphide bridges formed during the crosslinking process. In another paper, the characterization and optimization of PLA in in-situ forming hydrogels (that exhibited a sol-to-gel transition between room and body temperatures), composed of PEI/DNA multi-layered micelles, for local gene delivery systems was described [14]. The investigation of their degradation profiles and chemical analysis indicated the faster acidic degradation and stepwise degradation process of these micelle-hydrogel systems.…”