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RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated liposomes for enhanced intracellular drug delivery to hepsin-expressing cancer cells.

AbstractBACKGROUND:
To facilitate selective drug delivery to hepsin (Hpn)-expressing cancer cells, the RIPL peptide (IPLVVPLRRRRRRRRC; 16mer; 2.1 kDa) was synthesized as a novel cell penetrating/homing peptide (CPHP) and conjugated to a liposomal carrier.
METHODS:
RIPL peptide-conjugated liposomes (RIPL-Lipo) were prepared by conjugating RIPL peptides to maleimide-derivatized liposomal vesicles via the thiol-maleimide reaction. Vesicle size and zeta potential were examined using a Zetasizer. Intracellular uptake specificity of the RIPL peptide, or RIPL-Lipo, was assessed by measuring mean fluorescence intensity (MFI) after treatment with a fluorescent marker in various cell lines: SK-OV-3, MCF-7, and LNCaP for Hpn(+); DU145, PC3, and HaCaT for Hpn(-). FITC-dextran was used as a model compound. Selective translocational behavior of RIPL-Lipo to LNCaP cells was visualized by fluorescence microscopy and confocal laser scanning microscopy. Cytotoxicities of the RIPL peptide and RIPL-Lipo were evaluated by WST-1 assay.
RESULTS:
RIPL peptides exhibited significant Hpn-selectivity. RIPL-Lipo systems were of positively charged nanodispersion (165 nm in average; 6-24 mV depending on RIPL conjugation ratio). RIPL-Lipo with the conjugation of 2300 peptide molecules revealed the greatest MFI in all cell lines tested. Cellular uptake of RIPL-Lipo increased by 20- to 70-fold in Hpn(+) cells, and 5- to 7-fold in Hpn(-) cells, compared to the uptake of FITC-dextran. Cytosolic internalization of RIPL-Lipo was time-dependent: bound instantly; internalized within 30 min; distributed throughout the cytoplasm after 1 h. Cytotoxicities of RIPL peptide (up to 50 μM) and RIPL-Lipo (up to 10%) were minor (cell viability >90%) in LNCaP and HaCaT cells.
CONCLUSION:
By employing a novel CPHP, the RIPL-Lipo system was successfully developed for Hpn-specific drug delivery.
AuthorsMin Hyung Kang, Min Jung Park, Hyun Joon Yoo, Kwon Yie hyuk, Sang Gon Lee, Sung Rae Kim, Dong Woo Yeom, Myung Joo Kang, Young Wook Choi
JournalEuropean journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 87 Issue 3 Pg. 489-99 (Aug 2014) ISSN: 1873-3441 [Electronic] Netherlands
PMID24704199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Drug Carriers
  • Liposomes
  • Maleimides
  • Peptides
  • maleimide
  • Serine Endopeptidases
  • hepsin
Topics
  • Cell Line, Tumor
  • Drug Carriers (administration & dosage)
  • Drug Delivery Systems
  • Humans
  • Liposomes (administration & dosage)
  • MCF-7 Cells
  • Maleimides (administration & dosage)
  • Microscopy, Fluorescence (methods)
  • Peptides (administration & dosage)
  • Serine Endopeptidases (metabolism)

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