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
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.
- SourceAvailable from: Adeel Gulzar Chaudhary
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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   . To date, various TAT fusion proteins have been investigated for the treatment of NDDs . "
ABSTRACT: Neurodegeneration is the progressive loss of structure or function of neurons leading to neuronal death, usually associated with ageing. Some of the common neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Huntington's disease. Due to recent advancements in high-throughput technologies in various disciplines such as genomics, epigenomics, metabolomics and proteomics, there has been a great demand for detection of specific macromolecules such as hormones, drug residues, miRNA, DNA, antibodies, peptides, proteins, pathogens and xenobiotics at nano-level concentrations for in-depth understanding of disease mechanisms as well as for the development of new therapeutic strategies. The present review focuses on the management of age-related neurodegenerative disorders using proteomics and nanotechnological approaches. In addition, this review also highlights the metabolism and disposition of nano-drugs and nano-enabled drug delivery in neurodegenerative disorders.Current Drug Metabolism 12/2014; · 3.49 Impact Factor
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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. "
ABSTRACT: Vivo-morpholinos are commercially available morpholino oligomers with a terminal octa-guanidinium dendrimer for enhanced cell-permeability. Existing evidence from systemically delivered vivo-morpholinos indicate that genetic suppression can last from days to weeks without evidence of cellular toxicity. However, intravenously delivered vivo-morpholinos are ineffective at protein suppression in the brain, and no evidence is available regarding whether intracranially delivered vivo-morpholinos effectively reduce target protein levels, or do so without inducing neurotoxicity. Here we report examples in which in vivo microinjection of antisense vivo-morpholinos directed against three different targets (xCT, GLT1, orexin) in two different brain regions resulted in significant suppression of protein expression without neurotoxicity. Expression was significantly suppressed at six to seven days post-administration, but returned to baseline levels within fourteen days. These results indicate that direct intracranial administration of vivo-morpholinos provides an effective means by which to suppress protein expression in the brain for one to two weeks.Journal of neuroscience methods 01/2012; 203(2):354-60. DOI:10.1016/j.jneumeth.2011.10.009 · 1.96 Impact Factor
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- "In summary, CPPs define an extremely efficient delivery system, emphasized by their ability to allow macromolecular translocation within multiple tissues in vivo upon systemic administration  and the capability of inducing cell penetration within 100% of cells of a given cell culture population . Consequently, this efficiency offers great potential for the application of CPP technology to siRNA delivery, which for all practical purposes should be thought of as a macromolecule. "
ABSTRACT: Macromolecular nanoparticles can extravasate and accumulate within tumor tissues via the passive targeting system, reflecting enhanced permeability and the retention effect. However, the unsatisfactory tumor therapeutic efficacy of the passive-targeting system, attributable to the retention of extravasated nanoparticles in the vicinity of tumor vessels, argues that a new system that facilitates intracellular delivery of nanoparticles within tumors is needed. Here, we developed hydrophobically modified glycol chitosan (HGC) nanoparticles conjugated with interleukin-4 receptor (IL-4R) binding peptides, termed I4R, and tested them in mice bearing IL-4R-positive tumors. These HGC-I4R nanoparticles exhibited enhanced IL-4R-dependent cellular uptake in tumors compared to nonconjugated nanoparticles, leading to better therapeutic and imaging efficacy. We conclude that I4R facilitates and enhances cellular uptake of nanoparticles in tumor tissues. This study suggests that the intracelluar uptake of nanoparticles in tumors is an essential factor to consider in designing nanoparticles for tumor-targeted drug delivery and imaging.Journal of Controlled Release 09/2011; 157(3):493-9. DOI:10.1016/j.jconrel.2011.09.070 · 7.26 Impact Factor