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• W2059624781 abstract "Several cationic antimicrobial peptides have been investigated as potential anti-cancer drugs due to their demonstrated selective toxicity towards cancer cells relative to normal cells. For example, intracellular delivery of KLA, a pro-apoptotic peptide, results in toxicity against a variety of cancer cell lines; however, the relatively low activity and small size lead to rapid renal excretion when applied in vivo, limiting its therapeutic potential. In this work, apoptotic peptide–polymer hybrid materials were developed to increase apoptotic peptide activity via multivalent display. Multivalent peptide materials were prepared with comb-like structure by RAFT copolymerization of peptide macromonomers with N-(2-hydroxypropyl) methacrylamide (HPMA). Polymers displayed a GKRK peptide sequence for targeting p32, a protein often overexpressed on the surface of cancer cells, either fused with or as a comonomer to a KLA macromonomer. In three tested cancer cell lines, apoptotic polymers were significantly more cytotoxic than free peptides as evidenced by an order of magnitude decrease in IC50 values for the polymers compared to free peptide. The uptake efficiency and intracellular trafficking of one polymer construct was determined by radiolabeling and subcellular fractionation. Despite their more potent cytotoxic profile, polymeric KLA constructs have poor cellular uptake efficiency (< 1%). A significant fraction (20%) of internalized constructs localize with intact mitochondrial fractions. In an effort to increase cellular uptake, polymer amines were converted to guanidines by reaction with O-methylisourea. Guanidinylated polymers disrupted function of isolated mitochondria more than their lysine-based analogs, but overall toxicity was decreased, likely due to inefficient mitochondrial trafficking. Thus, while multivalent KLA polymers are more potent than KLA peptides, these materials can be substantially improved by designing next generation materials with improved cellular internalization and mitochondrial targeting efficiency." @default.
• W2059624781 created "2016-06-24" @default.
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• W2059624781 date "2015-05-01" @default.
• W2059624781 modified "2023-10-15" @default.
• W2059624781 title "Multivalent display of pendant pro-apoptotic peptides increases cytotoxic activity" @default.
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• W2059624781 doi "https://doi.org/10.1016/j.jconrel.2015.01.013" @default.
• W2059624781 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4395534" @default.
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