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An artificial virus-like nano carrier system: enhanced endosomal escape of nanoparticles via synergistic action of pH-sensitive fusogenic peptide derivatives

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Abstract

We previously reported that transferrin (Tf)-modified liposomes (Tf-L) additionally modified with a cholesterylated pH-sensitive fusogenic peptide (Chol-GALA) can release an encapsulated aqueous phase marker to cytosol via endosomal membrane fusion. However, further obstacles need to be overcome to bring the Tf-L to the level of a viral-like gene delivery system. In this study, we developed a novel packaging method to encapsulate condensed plasmid DNA into PEgylated Tf-L (Tf-PEG-L) to form a core–shell-type nanoparticle. The most difficult challenge was to provide a mechanism of escape for the condensed core from endosome to cytosol in the presence of polyethylene glycol (PEG). We hypothesized that a membrane-introduced Chol-GALA and a PEgylated GALA would interact synergistically to induce membrane fusion between liposome and endosome. By simultaneously incorporating Chol-GALA into the membrane of Tf-PEG-L and GALA at tips of PEG chains, a condensed core was released into cytosol, and transfection acitivty increased 100-fold. We concluded that topological control was responsible for the synergistic effect of GALA derivatives introduced on Tf-PEG-L.

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Abbreviations

Chol:

Cholesterol

Chol-GALA:

Cholesteryl-GALA

CLSM:

Confocal laser scanning microscopy

DCP:

Dicetylphosphate

DOPE:

Dioleoyl phosphatidylethanolamine

DPC:

DNA/polycation complex

DSPE-PEG2000:

Distearyl phosphatidyl ethanolamine-polyethylenglycol 2000

EPC:

Egg phosphatidylcholine

FITC:

Fluorescein isothiocyanate

HA:

Hemagglutinin

MEND:

Multifunctional envelope-type nanodevice

NBD-DOPE:

4-Nitrobenzo-2-oxa-1,3-diazolyl-DOPE

N/P:

Nitrogen/phosphate

OGP:

n-Octyl β-D-glucopyranoside

pDNA:

Plasmid DNA

PDP-PE:

N-[3-(2-pyridyldithio)propionate]-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine

PEG-GALA:

PEgylated GALA

PLL:

Poly-L-lysine

Rho-DOPE:

Lissamine rhodamine B-DOPE

SPDP:

3-(2-Pyridyldithio)propionic acid N-hydroxysuccinimide ester

S-Rh:

Sulforhodamine B

SUV*:

Detergent-rich small unilamellar vesicle

Tf:

Transferrin

Tf-L:

Tf-modified liposomes

Tf-PEG-L:

PEgylated Tf-L

Tf-PEG-L(Chol-GALA):

Tf-PEG-L modified with Chol-GALA

Tf-PEG-L(Chol&PEG-GALA):

Tf-PEG-L modified with Chol-GALA and PEG-GALA

Tf-PEG-L(PEG-GALA):

Tf-PEG-L modified with PEG-GALA

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Acknowledgements

This work was supported, in part, by Grants-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Grants-in-Aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science. The authors wish to thank Dr. Daryl Henderson for his helpful advice in writing the English manuscript.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, 060-0812, Japan

    Kentaro Sasaki, Shinji Chaki, Yoshio Nakamura, Rumiko Moriguchi & Hideyoshi Harashima

  2. CREST, Japan Science and Technology Agency (JST), Kawaguchi Center Building 4-1-8, Honcho, Kawaguchi-shi, Saitama, 332-0012, Japan

    Kentaro Sasaki, Shinji Chaki & Hideyoshi Harashima

  3. Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, Kyoto, 607-8414, Japan

    Kentaro Kogure

  4. Department of Molecular Medicine, Sapporo Medical University, Minami 1 Nishi 17, Chuo-ku, Sapporo, 060-8556, Japan

    Hirofumi Hamada

  5. Okazaki Institute for Integrative Bioscience, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi, 444-8787, Japan

    Radostin Danev & Kuniaki Nagayama

  6. Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan

    Shiroh Futaki

  7. PRESTO, Japan Science and Technology Agency (JST), Kawaguchi Center Building 4-1-8, Honcho, Kawaguchi-shi, Saitama, 332-0012, Japan

    Shiroh Futaki

  8. Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, 060-0812, Japan

    Hideyoshi Harashima

Authors
  1. Kentaro Sasaki
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  2. Kentaro Kogure
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  3. Shinji Chaki
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  4. Yoshio Nakamura
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  5. Rumiko Moriguchi
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  6. Hirofumi Hamada
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  7. Radostin Danev
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  8. Kuniaki Nagayama
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  9. Shiroh Futaki
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  10. Hideyoshi Harashima
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Corresponding author

Correspondence to Hideyoshi Harashima.

Additional information

Kentaro Sasaki and Kentaro Kogure contributed equally to this work.

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Sasaki, K., Kogure, K., Chaki, S. et al. An artificial virus-like nano carrier system: enhanced endosomal escape of nanoparticles via synergistic action of pH-sensitive fusogenic peptide derivatives. Anal Bioanal Chem 391, 2717–2727 (2008). https://doi.org/10.1007/s00216-008-2012-1

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  • DOI: https://doi.org/10.1007/s00216-008-2012-1

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