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Wadia, J.S. & Dowdy, S.F. Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. Adv. Drug Deliv. Rev. 57, 579-596

Howard Hughes Medical Institute, and Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, California 92093-0686, USA.
Advanced Drug Delivery Reviews (Impact Factor: 12.71). 03/2005; 57(4):579-96. DOI: 10.1016/j.addr.2004.10.005
Source: PubMed

ABSTRACT The direct intracellular delivery of proteins, or active peptide domains, has, until recently, been difficult to achieve due primarily to the bioavailability barrier of the plasma membrane, which effectively prevents the uptake of macromolecules by limiting their passive entry. Traditional approaches to modulate protein function have largely relied on the serendipitous discovery of specific drugs and small molecules which could be delivered easily into the cell. However, the usefulness of these pharmacological agents is limited by their tissue distribution and unlike 'information-rich' macromolecules, they often suffer from poor target specificity, unwanted side-effects, and toxicity. Likewise, the development of molecular techniques, over the past several decades, for gene delivery and expression of proteins has provided for tremendous advances in our understanding of cellular processes but has been of surprisingly little benefit for the management of genetic disorders. Apart from these gains however, the transfer of genetic material into eukaryotic cells either using viral vectors or by non-viral mechanisms such as microinjection, electroporation, or chemical transfection remains problematic. Moreover, in vivo, gene therapy approaches relying on adenoviral vectors are associated with significant difficulties relating to a lack of target specificity and toxicity which have contributed to poor performance in several clinical trials. Remarkably, the recent identification of a particular group of proteins with enhanced ability to cross the plasma membrane in a receptor-independent fashion has led to the discovery of a class of protein domains with cell membrane penetrating properties. The fusion of these protein transduction domain peptide sequences with heterologous proteins is sufficient to cause their rapid transduction into a variety of different cells in a rapid, concentration-dependent manner. Moreover, this novel technique for protein and peptide delivery appears to circumvent many problems associated with DNA and drug based methods. This technique may represent the next paradigm in our ability to modulate cell function and offers a unique avenue for the treatment of disease.

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    • "PTDs can be used in several ways. They can be introduced into protein by chemical conjugation method or alternatively, can be geneticallyfused to the protein cDNA and expressed in host mammalian cells via transfection or they can also be produced in bacteria even though the mechanism of transduction still remains unknown [112] [114] [115]. To date, various TAT fusion proteins have been investigated for the treatment of NDDs [116]. "
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    • "In this case, the dendrimer is formed by the presence of either octa-guanidinium groups. This terminal attachment allows for facilitated cell permeability, via chemistry similar to that employed by TAT and other related peptide membrane permeability domains (Wadia and Dowdy, 2005). While vivomorpholinos are superior to non-conjugated morpholinos for achieving suppression following i.v. "
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