DOI: 10.1073/pnas.1715350115
论文题名: Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors
作者: Wyatt L.C. ; Moshnikova A. ; Crawford T. ; Engelman D.M. ; Andreev O.A. ; Reshetnyak Y.K.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2018
卷: 115, 期: 12 起始页码: E2811
结束页码: E2818
语种: 英语
英文关键词: Cytoplasmic drug delivery
; Membrane-associated folding
; Polar drugs
; Targeted chemotherapy
; Tumor acidity
Scopus关键词: 4 carboxyglutamic acid
; alpha amanitin
; antineoplastic agent
; fluorophore peptide conjugate
; glycine
; leucine
; macrogol
; peptide
; pH low insertion peptide
; unclassified drug
; amanitin
; antineoplastic agent
; liposome
; membrane protein
; peptide
; pHLIP protein
; adult
; animal experiment
; animal model
; animal tissue
; Article
; breast cancer
; cell viability assay
; circular dichroism
; controlled study
; cytotoxicity
; drug delivery system
; drug distribution
; drug mechanism
; female
; fluorescence analysis
; in vitro study
; in vivo study
; lipid bilayer
; molecularly targeted therapy
; mouse
; mouse model
; nonhuman
; peptide analysis
; pH measurement
; priority journal
; protein motif
; steady state
; animal
; Bagg albino mouse
; chemistry
; drug delivery system
; experimental neoplasm
; genetics
; HeLa cell line
; human
; pH
; procedures
; tissue distribution
; Amanitins
; Animals
; Antineoplastic Agents
; Circular Dichroism
; Drug Delivery Systems
; Female
; HeLa Cells
; Humans
; Hydrogen-Ion Concentration
; Lipid Bilayers
; Liposomes
; Membrane Proteins
; Mice, Inbred BALB C
; Neoplasms, Experimental
; Peptides
; Polyethylene Glycols
; Tissue Distribution
英文摘要: 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, cellimpermeable 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. © 2018 National Academy of Sciences. All rights reserved. Citation statistics:
资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163733
Appears in Collections: 气候变化与战略
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作者单位: Wyatt, L.C., Physics Department, University of Rhode Island, Kingston, RI 02881, United States; Moshnikova, A., Physics Department, University of Rhode Island, Kingston, RI 02881, United States; Crawford, T., Physics Department, University of Rhode Island, Kingston, RI 02881, United States; Engelman, D.M., Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, United States; Andreev, O.A., Physics Department, University of Rhode Island, Kingston, RI 02881, United States; Reshetnyak, Y.K., Physics Department, University of Rhode Island, Kingston, RI 02881, United States
Recommended Citation:
Wyatt L.C.,Moshnikova A.,Crawford T.,et al. Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors[J]. Proceedings of the National Academy of Sciences of the United States of America,2018-01-01,115(12)