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An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery.

Cell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function... Full description

Journal Title: International journal of nanomedicine 2015, Vol.10, pp.6199-6214
Main Author: Ding, Yuan
Other Authors: Sun, Dan , Wang, Gui-Ling , Yang, Hong-Ge , Xu, Hai-Feng , Chen, Jian-Hua , Xie, Ying , Wang, Zhi-Qiang
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1178-2013 ; DOI: 10.2147/IJN.S92519
Link: http://search.proquest.com/docview/1727990237/?pq-origsite=primo
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title: An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery.
format: Article
creator:
  • Ding, Yuan
  • Sun, Dan
  • Wang, Gui-Ling
  • Yang, Hong-Ge
  • Xu, Hai-Feng
  • Chen, Jian-Hua
  • Xie, Ying
  • Wang, Zhi-Qiang
subjects:
  • Animals–Administration & Dosage
  • Antibiotics, Antineoplastic–Pharmacokinetics
  • Breast Neoplasms–Pharmacology
  • Cell-Penetrating Peptides–Drug Therapy
  • Doxorubicin–Pathology
  • Drug Carriers–Chemistry
  • Drug Delivery Systems–Administration & Dosage
  • Female–Pharmacokinetics
  • Flow Cytometry–Pharmacology
  • Humans–Chemistry
  • Hydrazones–Chemistry
  • Hydrogen-Ion Concentration–Chemistry
  • Liposomes–Chemistry
  • Male–Chemistry
  • Mice–Chemistry
  • Mice, Inbred Balb C–Chemistry
  • Mice, Nude–Chemistry
  • Polyethylene Glycols
ispartof: International journal of nanomedicine, 2015, Vol.10, pp.6199-6214
description: Cell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG) and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL) to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR) to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS) was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into targeted subcellular compartments while remaining inactive and free from opsonins at a maximum extent in systemic circulation. The 4% CPPL as a drug delivery system will have great potential in the clinical application of anticancer drugs in future. Keywords: long circulation, pharmacokinetics, lysosome escape, nanocarrier, pH-sensitive liposomes
language: eng
source:
identifier: E-ISSN: 1178-2013 ; DOI: 10.2147/IJN.S92519
fulltext: fulltext
issn:
  • 11782013
  • 1178-2013
url: Link


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titleAn efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery.
creatorDing, Yuan ; Sun, Dan ; Wang, Gui-Ling ; Yang, Hong-Ge ; Xu, Hai-Feng ; Chen, Jian-Hua ; Xie, Ying ; Wang, Zhi-Qiang
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identifierE-ISSN: 1178-2013 ; DOI: 10.2147/IJN.S92519
subjectAnimals–Administration & Dosage ; Antibiotics, Antineoplastic–Pharmacokinetics ; Breast Neoplasms–Pharmacology ; Cell-Penetrating Peptides–Drug Therapy ; Doxorubicin–Pathology ; Drug Carriers–Chemistry ; Drug Delivery Systems–Administration & Dosage ; Female–Pharmacokinetics ; Flow Cytometry–Pharmacology ; Humans–Chemistry ; Hydrazones–Chemistry ; Hydrogen-Ion Concentration–Chemistry ; Liposomes–Chemistry ; Male–Chemistry ; Mice–Chemistry ; Mice, Inbred Balb C–Chemistry ; Mice, Nude–Chemistry ; Polyethylene Glycols
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descriptionCell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG) and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL) to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR) to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS) was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into targeted subcellular compartments while remaining inactive and free from opsonins at a maximum extent in systemic circulation. The 4% CPPL as a drug delivery system will have great potential in the clinical application of anticancer drugs in future. Keywords: long circulation, pharmacokinetics, lysosome escape, nanocarrier, pH-sensitive liposomes
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authorDing, Yuan ; Sun, Dan ; Wang, Gui-Ling ; Yang, Hong-Ge ; Xu, Hai-Feng ; Chen, Jian-Hua ; Xie, Ying ; Wang, Zhi-Qiang
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