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A Photo-Activated Targeting Chemotherapy Using Glutathione Sensitive Camptothecin-Loaded Polymeric Micelles

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Abstract

Purpose

A novel photo-activated targeted chemotherapy was developed by photochemical internalization (PCI) of glutathione-sensitive polymeric micelles incorporating camptothecin (CPT) prepared from thiolated CPT (CPT-DP) and thiolated poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-P(Glu-DP))

Methods

PEG-b-P(Glu-DP) and CPT-DP were synthesized and characterized by 1H-NMR and gel permeation chromatography, and then mixed to prepare CPT-loaded polymeric micelles (CPT/m). The CPT release from the micelle was studied by reverse phase liquid chromatography. The PCI-activated cytotoxicity of CPT/m against HeLa cells was studied in combination with a non-toxic concentration of dendrimer phthalocyanine-loaded micelles (DPc/m) as the photosensitizer.

Results

The diameter of CPT/m was 96 nm and the drug loading was 20% (w/w). CPT was slowly released under the conditions reproducing the extracellular or endosomal environments. However, under the reductive conditions mimicking the cytosol, CPT was rapidly released achieving approximately 90% of the drug release after 24 h. The cytotoxicity of CPT/m was drastically increased on photoirradiation, whereas the CPT/m were not cytotoxic without PCI.

Conclusions

The CPT/m released the drug responding to reductive conditions. The PCI-induced endosomal escape exposed CPT/m to the cytosol triggering the drug release. Thus, CPT/m in combination with DPc/m will behave as smart nanocarriers activated only at photoirradiated tissues.

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Abbreviations

CPT:

camptothecin

CPT-DP:

thiolated CPT

PEG-b-P(Glu-DP):

thiolated poly(ethylene glycol)-b-poly(glutamic acid)

CPT/m:

CPT-loaded polymeric micelles

DLS:

dynamic light scattering

DPc/m:

dendrimer phthalocyanine-loaded micelles

PCI:

photochemical internalization

PDT:

photodynamic therapy

PS:

photosensitizer

SPTDP:

disulfide amine linker

RPLC:

reverse phase liquid chromatography

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ACKNOWLEDGEMENT

This research was supported in part by the New Energy and Industrial Technology Development Organization of Japan (project code: P06042), Grant-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology as well as Grant-in-Aid for Cancer Research and Nanomedicine projects from Ministry of Health, labour and Welfare, Japan.

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Authors and Affiliations

  1. Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan

    Masataka Nakanishi & Kazunori Kataoka

  2. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Horacio Cabral, Michiaki Kumagai, Nobuhiro Nishiyama & Kazunori Kataoka

  3. Center for NanoBio Integration, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan

    Nobuhiro Nishiyama & Kazunori Kataoka

  4. Department of Chemistry, College of Science, Yonsei University, Seoul, South Korea

    Woo-Dong Jang

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  1. Horacio Cabral
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  2. Masataka Nakanishi
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  3. Michiaki Kumagai
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  4. Woo-Dong Jang
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  5. Nobuhiro Nishiyama
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  6. Kazunori Kataoka
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Correspondence to Kazunori Kataoka.

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Cabral, H., Nakanishi, M., Kumagai, M. et al. A Photo-Activated Targeting Chemotherapy Using Glutathione Sensitive Camptothecin-Loaded Polymeric Micelles. Pharm Res 26, 82–92 (2009). https://doi.org/10.1007/s11095-008-9712-2

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  • DOI: https://doi.org/10.1007/s11095-008-9712-2

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