Progress and perspectives in developing polymeric vectors for in vitro gene delivery

Abstract

The development of safe, efficient and controllable gene-delivery vectors has become a bottleneck to human gene therapy. Synthetic polymeric vectors, although safer than viral carriers, generally do not possess the required efficacy, apparently due to a lack of functionality to overcome at least one of many intracellular gene-delivery obstacles. Currently, the exact mechanisms of how these polymeric vectors navigate each intracellular obstacle ("slit"), as well as their particular physical/chemical properties that contribute to efficient intracellular trafficking remain largely unknown, making it rather difficult to further improve the efficacy of non-viral polymeric vectors in vitro and in vivo. In this review, we first give a brief overview of synthetic polymeric vectors that have been designed and developed for gene delivery and highlight some promising candidates for clinical applications. Our main focus is on discussing the intracellular trafficking mechanisms of the DNA-polymer complexes ("polyplexes"), with less effort on the DNA-polymer complexation in the extracellular space as well as the in vivo systemic administration of genes in animal models and human clinical trials. In particular, we identified and discussed four critical, YananYUE received her B.S. degree in Polymer Materials and Engineering from Zhejiang University in 2007 and her Ph.D. in Chemistry at the Chinese University of Hong Kong, under the supervision of Professor Chi WU. Her research interests mainly focus on the development of nonviral vectors for molecular medicines, especially the effect of free polycationic chains on the intracellular trafficking of DNApolymer complexes in gene transfection. She is now working in the Department of Chemistry, the University of Chicago, under the supervision of Professor Chuan HE. Chi WU graduated from the Department of Chemical Physics at the University of Science and Technology of China (USTC) in 1982. After obtaining his Ph.D. in 1987 followed by two-year postdoctoral experience under the supervision of Professor Benjamin Chu in the State University of New York at Stony Brook, he moved to BASF (Ludwigshafen, Germany) in 1989; first as an Alexander von Humboldt Fellow for one year with Dr. Dieter Horn and then as the supervisor of laser light-scattering laboratory. In 1992, he resigned from BASF and joined the Department of Chemistry at the Chinese University of Hong Kong (CUHK) as a Lecturer. He underwent a double promotion directly to Reader in 1996; and became a Chair Professor of Chemistry and Honorary Professor of Physics in 1999. Recently, he has been appointed as a Wei Lun Chair Professor of Chemistry since 2010.

Effect of peptide content on the regulation of transgene expression by protein kinase Cα-responsive linear polyethylenimine-peptide conjugates

“…Polymeric gene carriers have attracted attention for potential applications in the field of gene therapy, especially for cancer treatment [1][2][3]. Various polymers, including linear/branched polyethylenimine (PEI) [4,5], polysaccharides [6], polypeptide [7], block copolymers [8], and branched polymers [9,10] have been investigated as gene carriers for cancer treatment.…”

Synthesis and NMR characterization of dendrimers based on 2, 2-bis-(hydroxymethyl)-propanoic acid (bis-HMPA) containing peripheral amino acid residues for gene transfection

“…These varied characteristics make dendrimers "nonpareil" materials and to date, they represent a good choice in the medical field and for biomedical applications such as drug delivery nanocarriers, 3 biosensors, 4,5 bio imaging agents 6 and theranostics. 7 Dendrimers containing nitrogen atoms, which can be protonated at physiological pH, are deeply investigated as non-viral polymeric vectors [8][9][10][11][12][13][14][15][16][17] for delivering nucleic acids into specific cell of patients to replace defective genes (gene therapy). Protonated dendrimers, like other cationic polymeric systems, can establish in fact electrostatic interactions with phosphate groups of genetic materials, promoting the formation of nanoparticles known as "polyplexes" where the polymeric component can protect the therapeutic genes from degradation by nucleases during trafficking to the nucleus 10 and successively release them, if the binding strength of the two components of the polyplex are not too strong.…”

Recent progress in gene therapy to deliver nucleic acids with multivalent cationic vectors

“…1c-d). Since commercial cationic polymers were initially used to deliver nucleic acids with poorly results [79,80], the effort addressed to synthesize more efficient compacting and transfecting cationic polymer-based vectors have increased specially in the last decade [14,39]. Typically, the headgroup of cationic polymers is amine-based because it is protonable at physiological pH.…”

“…These were mainly directed to specific aspects of the compaction process, as the molecular characteristics of the hydrophobic regions and/or headgroups, and of the lipoplex structure [11,15,[20][21][22][23][24][25], the biochemical behavior [26][27][28][29][30], the structure-biological activity relationship [9,21,[31][32][33][34][35], or to several of them [7,8,10,13,36,37]. On the other hand, several reviews have been centered in polyplexes [14,[38][39][40][41] or in a wide variety of nanocarriers [16,17,[42][43][44]. The present review summarizes the biophysics and biochemistry studies carried on in the present decade with multivalent cationic gene vectors.…”