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Design of "Smart" Nano-Scale Delivery Systems for Biomolecular Therapeutics

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Abstract:

This article begins with a brief review of the principles of drug delivery, with special focus on drug delivery applications in tissue engineering implants. It follows with examples of our work to develop biomimetic, nano-scale delivery systems for intracellular delivery of "fragile" macromolecular therapeutics such as plasmid DNA, antisense oligodeoxynucleotides (AS-ODN), silencing RNA (siRNA or RNAi) and protein and peptide drugs. Our approach to develop biomimetic systems is based on the biomolecular mechanism that many viruses and pathogens use to deliver their bioactive cargoes to the cytoplasm of target cells. Specific peptide sequences found in the protein coats of some viruses and pathogens become hydrophobic in response to the lowered pH of the endosomal compartment. These sequences then "fuse" with the lipid bilayer of the endosomal membrane, enhancing the escape of viral DNA or RNA or toxic protein (from the pathogen) to the cytoplasmic compartment. We have designed and synthesized polymers that mimic this action of the fusogenic peptide sequences, and have incorporated them into nano-scale delivery systems for intracellular delivery of nucleic acid and protein drugs. The key feature of these polymers is their ability to enhance the cytosolic delivery of nucleic acid and protein drugs from the endosome by destabilizing endosomal membranes in response to pH changes within the endosome. In this way such fragile drugs avoid being trafficked to the lysosome, where the lysosomal enzymes would destroy their activity. The ability to deliver these biomolecular drugs to the cytosol of cells that surround and/or are within tissue engineering scaffolds could greatly enhance control of important processes in regenerative medicine such as inflammation, angiogenesis, and cell differentiation and proliferation, thereby ultimately enhancing the desired regeneration of soft or hard tissue.

Keywords: ENDOSOMAL DRUG RELEASE; NUCLEI ACID DRUGS; PEPTIDE AND PROTEIN DRUGS; POLYMER-DRUG CONJUGATES AND COMPLEXES

Document Type: Review Article

DOI: https://doi.org/10.1166/jbn.2007.031

Publication date: 2007-09-01

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  • Journal of Biomedical Nanotechnology (JBN) is a peer-reviewed multidisciplinary journal providing broad coverage in all research areas focused on the applications of nanotechnology in medicine, drug delivery systems, infectious disease, biomedical sciences, biotechnology, and all other related fields of life sciences.
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