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• W2900067384 abstract "Endocytosed biomacromolecule delivery systems must escape the endosomal trafficking pathway in order for their cargo to exert effects in other cellular compartments. Although endosomal release is well-recognized as one of the greatest barriers to efficacy of biologic drugs with intracellular targets, most drug carriers have relied on cationic materials that passively induce endosomal swelling and membrane rupture with low efficiency. To address the endosome release challenge, our lab has developed a diblock copolymer system for nucleic acid delivery that selectively displays a potent membrane-lytic peptide (melittin) in response to the pH drop during the endosomal maturation. To further optimize this system, we evaluated a panel of peptides with reported lytic activity in comparison to melittin. Nineteen different lytic peptides were synthesized and their membrane-lytic properties at both neutral and acidic pH characterized using a red blood cell hemolysis assay. The top five performing peptides were then conjugated to our pH-sensitive diblock copolymer via disulfide linkers and used to deliver a variety of nucleic acids to cultured mammalian cells as well as in vivo to the mouse brain. We demonstrate that the sharp pH-transition of VIPER compensates for potential advantages from pH-sensitive peptides, such that polymer-peptide conjugates with poorly selective but highly lytic peptides achieve safe and effective transfection both in vitro and in vivo. In addition, peptides that require release from polymer backbones for lysis were less effective in the VIPER system, likely due to limited endosomal reducing power of target cells. Finally, we show that certain peptides are potentiated in lytic ability by polymer conjugation and that these peptide-polymer constructs are most effective in vivo." @default.
• W2900067384 created "2018-11-16" @default.
• W2900067384 creator A5001941506 @default.
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• W2900067384 creator A5055576209 @default.
• W2900067384 creator A5075083361 @default.
• W2900067384 creator A5082592471 @default.
• W2900067384 date "2019-02-01" @default.
• W2900067384 modified "2023-10-12" @default.
• W2900067384 title "pH-sensitive polymer micelles provide selective and potentiated lytic capacity to venom peptides for effective intracellular delivery" @default.
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• W2900067384 doi "https://doi.org/10.1016/j.biomaterials.2018.11.004" @default.
• W2900067384 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6331286" @default.
• W2900067384 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30458359" @default.
• W2900067384 hasPublicationYear "2019" @default.
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