Polymeric Controlled Nucleic Acid Delivery
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Polymeric Controlled Nucleic Acid Delivery Kam W. Leong Abstract Gene therapy harbors great promise for the treatment of a variety of inherited and acquired diseases, but its potential can be realized only with safe and effective carriers. Although viruses can efficiently transfer foreign genes to cells, their long-term safety remains a concern. Polymers can serve as a carrier to facilitate gene transfer, either by condensing DNA to the size of nanoparticles that can be internalized by cells, or by entrapping DNA in matrices or micro/nanoparticles for sustained release. However, polymeric controlled gene delivery remains highly inefficient. This review covers the major barriers for nonviral gene transfer and briefly describes the different types of polymers developed to overcome these barriers. With the tremendous promise of genetic medicine, nonviral gene delivery is a worthy goal for biomaterials and nanotechnology research. Keywords: biomedical materials, gene delivery, nanoparticles, nucleic acid delivery, polymeric.
Introduction Nucleic acids, in the form of antisense oligonucleotide (ODN),1 small interfering RNA (siRNA),2 or plasmid DNA, hold promise in treating a variety of inherited and acquired diseases. Their therapeutic potential is, however, limited by the lack of safe and efficient delivery vectors. This review focuses on the delivery of plasmid DNA, but the design principles would also be applicable for ODN and siRNA. Viruses remain the vectors of choice to achieve high-efficiency DNA transfer in vivo because of their natural mechanism of entering cells and transfecting a variety of cell types. However, reservations about their long-term safety are unlikely to abate in the near future.3–5 Issues of immunogenicity and toxicity remain a challenge. Limitations of cell mitosis for retroviruses, contamination of adenoviruses, and packaging constraints of adeno-associated viruses also lessen their appeal. Nonviral vectors, although achieving only transient and low gene expression levels, are receiving increasing attention on the basis of their ease of synthesis, low immunogenicity, and unrestricted plasmid size.6–11 They have the potential to be administered re-
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peatedly with minimal host immune response. Nonviral vectors also face less of a challenge than viral vectors in addressing pharmaceutical issues such as scale-up, storage stability, and quality control. Direct administration of naked DNA and administration of DNA mediated by electroporation (the creation of pores in a cell membrane using electrical current), ultrasound, high-pressure bombardment, cationic lipids, and polymers represent the different modalities of nonviral gene transfer. In this review, we will focus on the use of polymeric material as a gene carrier. The predominant role of a cationic polymeric gene carrier is to condense DNA to nanoparticles that can be internalized by cells. It also serves to protect the DNA from enzymatic degradation during transit from the extracellular space to the nucleus of the cell. Polymeric gene ca
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