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- W2006337007 abstract "Purpose: To develop a system to selectively target protein therapeutics to hypoxic cells. Materials and Methods: Hypoxia is a feature unique to the majority of solid tumors. We have developed a strategy to selectively target protein therapeutics to hypoxic cells. The approach is based on the prevention of protein degradation under hypoxic conditions and the promotion of protein degradation under aerobic conditions. HIF-1α, the hypoxia-inducible transcription factor, is exquisitely regulated in response to cellular oxygen levels through the various interactions of its oxygen-dependent degradation domain (ODD). We have constructed a tagged ODD domain to allow for ease of purification and kinetic assay. The chimeric proteins are additionally modified to contain the HIV protein transduction domain, TAT, allowing penetration into cells in vivo. Our initial objective has been to establish the efficacy of the delivery system and define the strictest amino acid sequence responsible for oxygen-dependent degradation. Results: We have demonstrated that HIV-TAT mediated protein transduction is an efficient method for introducing peptides/proteins into mammalian cells. Protein transduction is not affected by hypoxia. Once transduced, TAT-proteins are stable inside cells for at least 48 hours. In addition, we have expressed and purified mulitiple versions of tagged ODD and assessed their uptake efficiency in vivo. Definition of the ODD domain is under analysis. Conclusion: We have designed a system for regulating protein delivery to mammalian cells by exploiting the physiology of tissue hypoxia. Further efforts focus on tagging anticancer peptides/proteins with ODD to create potential hypoxic cell-specific therapeutics." @default.
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- W2006337007 date "2001-11-01" @default.
- W2006337007 modified "2023-09-27" @default.
- W2006337007 title "Improving the ODDs: protein delivery to hypoxic tissue" @default.
- W2006337007 doi "https://doi.org/10.1016/s0360-3016(01)01972-1" @default.
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