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Accelerated Blood Clearance Phenomenon Upon Repeated Injection of PEG-modified PLA-nanoparticles

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Abstract

Purpose

We recently developed prostaglandin E1 (PGE1)-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats.

Methods

The plasma levels of PGE1 and anti-PEG IgM antibody were determined by EIA and ELISA, respectively.

Results

Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE1 than NP-L20.

Conclusions

This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE1.

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Abbreviations

ABC:

Accelerated blood clearance

ADAM:

9-anthryldiazomethane

AUC:

Area under the blood concentration-time curve

CL:

Total body clearance

DEA:

diethanolamine

EPR:

Enhanced permeability and retention

FBS:

Fetal bovine serum

1H-NMR:

Proton nuclear magnetic resonance

HPLC:

High-performance liquid chromatography

MPS:

Mononuclear phagocyte system

MQW:

Milli-Q water

Mw:

Molecular weight

PBS:

Phosphate-buffered saline

PEG:

Poly(ethyleneglycol)

PGE1:

Prostaglandin E1

PLA:

Poly(lactide)

QOL:

Quality of life

S.E.M.:

Standard error mean

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ACKNOWLEDGEMENTS

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour, and Welfare of Japan, as well as the Japan Science and Technology Agency and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan

    Tsutomu Ishihara, Miho Takeda, Haruka Sakamoto, Ayumi Kimoto, Chisa Kobayashi, Naoko Takasaki, Kanae Yuki, Ken-ichiro Tanaka, Taishi Maeda, Naoki Yamakawa, Yoshinari Okamoto, Masami Otsuka & Tohru Mizushima

  2. DDS Institute, The Jikei University School of Medicine, Tokyo, 105-8461, Japan

    Tsutomu Ishihara & Yutaka Mizushima

  3. Division of Drug Delivery System, Institute of Medical Science, St. Marianna University, Kawasaki, 216-8512, Japan

    Mitsuko Takenaga & Rie Igarashi

  4. Institute of Health Bioscience, The University of Tokushima, Tokushima, 770-8505, Japan

    Tatsuhiro Ishida & Hiroshi Kiwada

Authors
  1. Tsutomu Ishihara
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  2. Miho Takeda
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  18. Tohru Mizushima
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Corresponding author

Correspondence to Tohru Mizushima.

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Ishihara, T., Takeda, M., Sakamoto, H. et al. Accelerated Blood Clearance Phenomenon Upon Repeated Injection of PEG-modified PLA-nanoparticles. Pharm Res 26, 2270–2279 (2009). https://doi.org/10.1007/s11095-009-9943-x

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  • DOI: https://doi.org/10.1007/s11095-009-9943-x

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