Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin a2ß1 receptor

Nina Østergaard Knudsen; Raymond M. Schiffelers; Lene Jørgensen; Jens Hansen; Sven Frøkjær; Camilla Foged

doi:10.1016/j.ijpharm.2012.02.043

Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin a₂ß₁receptor

Nina Østergaard Knudsen, Raymond M. Schiffelers, Lene Jørgensen, Jens Hansen, Sven Frøkjær, Camilla Foged

12 Citations (Scopus)

Abstract

Peptide conjugation to the surface of stealth liposomes has been studied for liposomal drug targeting to cells expressing specific receptors to provide a site-specific drug delivery. This study investigated the potential of peptide-conjugated liposomes for targeting cells expressing the human integrin α ₂β ₁ receptor. A 12 amino acid head-to-tail cyclic peptide derived from the Jararhagin protein containing the Arg-Lys-Lys-His (RKKH)-specific binding site was conjugated to the distal ends of poly(ethylene glycol) (PEG) chains on PEGylated liposomes. Epithelial cells expressing the receptor showed increased cellular association and uptake of peptide-conjugated liposomes at 4 °C, compared to liposomes conjugated with a non-specific peptide. The interaction between cells and peptide-conjugated liposomes was significantly increased at 37 °C suggesting that a possible uptake mechanism might be energy-dependent endocytosis. In keratinocyte cell cultures, the ligand-conjugated liposomes loaded with the vitamin D ₃ analogue calcipotriol induced transcription of the gene encoding the antimicrobial peptide cathelicidin, which is activated through the vitamin D ₃ receptor upon binding of vitamin D ₃ analogues. This suggests that the liposomes are internalized and that calcipotriol is delivered intracellularly and released in an active form. In conclusion, the 12 amino acid head-to-tail cyclic RKKH peptide seems promising for targeting of liposomes to the integrin α ₂β ₁ receptor.

Original language	English
Journal	International Journal of Pharmaceutics
Volume	428
Issue number	1-2
Pages (from-to)	171-177
ISSN	0378-5173
DOIs	https://doi.org/10.1016/j.ijpharm.2012.02.043
Publication status	Published - 30 May 2012

Keywords

Former Faculty of Pharmaceutical Sciences

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10.1016/j.ijpharm.2012.02.043

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@article{d0b9e8706df744689b50951b41763f8a,

title = "Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin a2{\ss}1 receptor",

abstract = "Peptide conjugation to the surface of stealth liposomes has been studied for liposomal drug targeting to cells expressing specific receptors to provide a site-specific drug delivery. This study investigated the potential of peptide-conjugated liposomes for targeting cells expressing the human integrin α 2β 1 receptor. A 12 amino acid head-to-tail cyclic peptide derived from the Jararhagin protein containing the Arg-Lys-Lys-His (RKKH)-specific binding site was conjugated to the distal ends of poly(ethylene glycol) (PEG) chains on PEGylated liposomes. Epithelial cells expressing the receptor showed increased cellular association and uptake of peptide-conjugated liposomes at 4 °C, compared to liposomes conjugated with a non-specific peptide. The interaction between cells and peptide-conjugated liposomes was significantly increased at 37 °C suggesting that a possible uptake mechanism might be energy-dependent endocytosis. In keratinocyte cell cultures, the ligand-conjugated liposomes loaded with the vitamin D 3 analogue calcipotriol induced transcription of the gene encoding the antimicrobial peptide cathelicidin, which is activated through the vitamin D 3 receptor upon binding of vitamin D 3 analogues. This suggests that the liposomes are internalized and that calcipotriol is delivered intracellularly and released in an active form. In conclusion, the 12 amino acid head-to-tail cyclic RKKH peptide seems promising for targeting of liposomes to the integrin α 2β 1 receptor.",

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author = "Knudsen, {Nina {\O}stergaard} and Schiffelers, {Raymond M.} and Lene J{\o}rgensen and Jens Hansen and Sven Fr{\o}kj{\ae}r and Camilla Foged",

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T1 - Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin a2ß1 receptor

AU - Knudsen, Nina Østergaard

AU - Schiffelers, Raymond M.

AU - Jørgensen, Lene

AU - Hansen, Jens

AU - Frøkjær, Sven

AU - Foged, Camilla

PY - 2012/5/30

Y1 - 2012/5/30

N2 - Peptide conjugation to the surface of stealth liposomes has been studied for liposomal drug targeting to cells expressing specific receptors to provide a site-specific drug delivery. This study investigated the potential of peptide-conjugated liposomes for targeting cells expressing the human integrin α 2β 1 receptor. A 12 amino acid head-to-tail cyclic peptide derived from the Jararhagin protein containing the Arg-Lys-Lys-His (RKKH)-specific binding site was conjugated to the distal ends of poly(ethylene glycol) (PEG) chains on PEGylated liposomes. Epithelial cells expressing the receptor showed increased cellular association and uptake of peptide-conjugated liposomes at 4 °C, compared to liposomes conjugated with a non-specific peptide. The interaction between cells and peptide-conjugated liposomes was significantly increased at 37 °C suggesting that a possible uptake mechanism might be energy-dependent endocytosis. In keratinocyte cell cultures, the ligand-conjugated liposomes loaded with the vitamin D 3 analogue calcipotriol induced transcription of the gene encoding the antimicrobial peptide cathelicidin, which is activated through the vitamin D 3 receptor upon binding of vitamin D 3 analogues. This suggests that the liposomes are internalized and that calcipotriol is delivered intracellularly and released in an active form. In conclusion, the 12 amino acid head-to-tail cyclic RKKH peptide seems promising for targeting of liposomes to the integrin α 2β 1 receptor.

AB - Peptide conjugation to the surface of stealth liposomes has been studied for liposomal drug targeting to cells expressing specific receptors to provide a site-specific drug delivery. This study investigated the potential of peptide-conjugated liposomes for targeting cells expressing the human integrin α 2β 1 receptor. A 12 amino acid head-to-tail cyclic peptide derived from the Jararhagin protein containing the Arg-Lys-Lys-His (RKKH)-specific binding site was conjugated to the distal ends of poly(ethylene glycol) (PEG) chains on PEGylated liposomes. Epithelial cells expressing the receptor showed increased cellular association and uptake of peptide-conjugated liposomes at 4 °C, compared to liposomes conjugated with a non-specific peptide. The interaction between cells and peptide-conjugated liposomes was significantly increased at 37 °C suggesting that a possible uptake mechanism might be energy-dependent endocytosis. In keratinocyte cell cultures, the ligand-conjugated liposomes loaded with the vitamin D 3 analogue calcipotriol induced transcription of the gene encoding the antimicrobial peptide cathelicidin, which is activated through the vitamin D 3 receptor upon binding of vitamin D 3 analogues. This suggests that the liposomes are internalized and that calcipotriol is delivered intracellularly and released in an active form. In conclusion, the 12 amino acid head-to-tail cyclic RKKH peptide seems promising for targeting of liposomes to the integrin α 2β 1 receptor.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.ijpharm.2012.02.043

DO - 10.1016/j.ijpharm.2012.02.043

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SN - 0378-5173

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JO - International Journal of Pharmaceutics

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