Gene therapy progress and prospects: synthetic polymer-based systems

Abstract

Low efficiency, significant toxicity, polymer polydispersity and poorly understood delivery mechanisms have initially plagued the field of polymer-based gene therapy. Numerous strategies have helped to improve polyplexes, including the development of biodegradable polymers with reduced toxicity, incorporation of cell targeting, surface shielding and additional transport domains for effective and specific delivery, or improved chemistry for syntheses of polymers with uniform size and topology. Combined biooptical imaging and bioinformatics, providing insights into transfer bottlenecks, have helped to design improved polyplexes. Bioresponsive multifunctional polymers adapt in a dynamic manner to delivery barriers for efficient transfer of pDNA or siRNA to the target site.

Polymer beacons for luminescence and magnetic resonance imaging of DNA delivery

“…The use of synthetic materials, such as polymers, for polynucleotide delivery has rapidly grown, and presents a wealth of promising alternatives to conventional viral vectors (3)(4)(5), which have caused serious problems in the clinic. Although much is known about the infection pathways, advantages, and troubles of viral vectors (6), researchers in the field of nonviral delivery are just beginning to understand the transfection mechanisms, benefits, and potential issues with the multitude of materials being developed as macromolecular drug carriers (7,8).…”

Intracellular delivery of VEGF165 encoding gene therapeutic using trifunctional copolymers of ethylene oxide and propylene oxide

“…A relatively high activity of Turbofect, which is poly(2-hydroxypropyleneimine) [30], could be explained by its ability to efficiently condense pDNA and promote its intracellular release from lysosomes due to their disruption by the cationic polymer ('proton sponge' effect). However, such characteristics of cationic polymers contribute to their high cytotoxicity [2,7], indicating the need to develop different polymeric systems for gene delivery. Our results demonstrate that TFCs can be used to enhance the transfection of human cells, presumably by promoting cellular uptake of pDNA complexes.…”

“…The main engineering platforms for gene therapeutics include synthetic oligonucleotides, viruses and plasmid DNAs (pDNA) [1,2], the two latter types are considered 'pro-drugs' that allow for a template-directed synthesis of a desired peptide within the cell. Compared to viruses, pDNA has a great advantage in clinical application due to its intrinsic safety, low cost and vector capacity.…”

“…However, the improvement of intrinsically low pDNA transfection efficiency remains relevant and unresolved biomedical task. The common approach exploits various cationic lipids and polymers, both of synthetic and natural origin, which bind to, condense and neutralize nucleic acids, thereby improving their stability and cellular pharmacokinetics [2,4].…”

“…While cationic carriers of pDNA exhibit a relatively high efficiency in vitro, their gene therapy applications are strictly restricted, due to membrane-damaging and cytotoxic properties of polycations [2,7]. To overcome this problem, new polymeric systems that deliver pDNA, both alone and combined with polycations, have been proposed.…”