Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications

Abstract

The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy has emerged as one of the most advanced, with the capability to tackle disorders from the modern era. However, there are several barriers associated with the delivery of genes in the living system that need to be mitigated by polymer engineering. One of the most crucial challenges is the effectiveness of the delivery vehicle or vector. In last few decades, non-viral delivery systems have gained attention because of their low toxicity, potential for targeted delivery, long-term stability, lack of immunogenicity, and relatively low production cost. In 1987, Felgner et al. used the cationic lipid based non-viral gene delivery system for the very first time. This breakthrough opened the opportunity for other non-viral vectors, such as polymers. Cationic polymers have emerged as promising candidates for non-viral gene delivery systems because of their facile synthesis and flexible properties. These polymers can be conjugated with genetic material via electrostatic attraction at physiological pH, thereby facilitating gene delivery. Many factors influence the gene transfection efficiency of cationic polymers, including their structure, molecular weight, and surface charge. Outstanding representatives of polymers that have emerged over the last decade to be used in gene therapy are synthetic polymers such as poly(l-lysine), poly(l-ornithine), linear and branched polyethyleneimine, diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). Natural polymers, such as chitosan, dextran, gelatin, pullulan, and synthetic analogs, with sophisticated features like guanidinylated bio-reducible polymers were also explored. This review outlines the introduction of polymers in medicine, discusses the methods of polymer synthesis, addressing top down and bottom up techniques. Evaluation of functionalization strategies for therapeutic and formulation stability are also highlighted. The overview of the properties, challenges, and functionalization approaches and, finally, the applications of the polymeric delivery systems in gene therapy marks this review as a unique one-stop summary of developments in this field.

Keywords: biodistribution; blood circulation of polymeric nanoparticles; cellular internalization of the polymeric nanoparticles; colloidal stability of polymeric nanoparticles; cytotoxicity; green chemistry; top down and bottom up synthesis.

Figure 1

Polymeric nanoparticles for the intracellular delivery of DNA and siRNA: (1) complexation of anionic DNA and siRNA with cationic polymers to form polyplexes (2) cellular uptake of polyplexes via different endocytic routes, (3) enclosure and subsequent release of polyplexes from endo-lysosomal compartments, (4) release of free DNA and siRNA from polyplexes leaving behind polymer remnants, and (5) transfer of DNA to the nucleus for expression by nuclear membrane transport proteins and binding of siRNA by RNA-induced silencing complex (RISC).

Figure 2

Summary of top-down and bottom-up techniques for generating polymeric nanoparticles.

Figure 3

Schematic representation of the solvent-evaporation technique. Reprinted with permission from Reference [53]. Copyright 2006 Elsevier.

Figure 4

Schematic representation of the nanoprecipitation (solvent displacement) technique. Reprinted with permission from Reference [53]. Copyright 2006 Elsevier.

Figure 5

Schematic representation of the salting out technique. Reprinted with permission from Reference [53]. Copyright 2006 Elsevier.

Figure 6

Schematic representation of an osmosis-based method for the preparation of polymer nanoparticles.

Figure 7

Experimental set-up for preparation of polymer nanoparticles via the rapid expansion of supercritical fluid solution. Reprinted with permission from Reference [73]. Copyright 2011 Elsevier.

Figure 8

Experimental set-up for the rapid expansion of supercritical fluid solution into liquid solvent process. Reprinted with permission from Reference [73]. Copyright 2011 Elsevier.

Figure 9

Schematic representation of the emulsification/solvent diffusion technique. Reprinted with permission from Reference [53]. Copyright 2006 Elsevier.

Figure 10

Summary of properties and challenges of polymeric nanoparticles for gene delivery and associated factors influencing each of these parameters.

Figure 11

Schematic illustration of non-invasive or minimally invasive routes of administration and targeting strategies for polymeric nanoparticles. From Reference [191], open access peer-reviewed edited volume, Copyright (2014) IntechOpen.

Figure 12

Chemical structure of biocleavable polyrotaxane: (a) polyplex formation and (b) terminal cleavage-triggered de-condensation of the polyplex. Reprinted with permission from Reference [210]. Copyright 2006 American Chemical Association.