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Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors
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Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors
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Journal Article
Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors
2018
Overview
The pH (low) insertion peptides (pHLIPs) target acidity at the surfaces of cancer cells and show utility in a wide range of applications, including tumor imaging and intracellular delivery of therapeutic agents. Here we report pHLIP constructs that significantly improve the targeted delivery of agents into tumor cells. The investigated constructs include pHLIP bundles (conjugates consisting of two or four pHLIP peptides linked by polyethylene glycol) and Var3 pHLIPs containing either the nonstandard amino acid, γ-carboxyglutamic acid, or a glycine−leucine−leucine motif. The performance of the constructs in vitro and in vivo was compared with previous pHLIP variants. A wide range of experiments was performed on nine constructs including (i) biophysical measurements using steady-state and kinetic fluorescence, circular dichroism, and oriented circular dichroism to study the pH-dependent insertion of pHLIP variants across the membrane lipid bilayer; (ii) cell viability assays to gauge the pH-dependent potency of peptide-toxin constructs by assessing the intracellular delivery of the polar, cell-impermeable cargo molecule amanitin at physiological and low pH (pH 7.4 and 6.0, respectively); and (iii) tumor targeting and biodistribution measurements using fluorophore-peptide conjugates in a breast cancer mouse model. The main principles of the design of pHLIP variants for a range of medical applications are discussed.
Publisher
National Academy of Sciences
Subject
/ Amanitin
/ Animals
/ Antineoplastic Agents - administration & dosage
/ Antineoplastic Agents - chemistry
/ Cancer
/ Drug Delivery Systems - methods
/ Female
/ Glycine
/ Humans
/ Leucine
/ Membrane Proteins - chemistry
/ Membrane Proteins - genetics
/ Neoplasms, Experimental - drug therapy
/ Peptides
/ Peptides - administration & dosage
/ Polyethylene Glycols - chemistry
/ Toxins
/ Tumors
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