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Preferential extravasation and accumulation of liposomal vincristine in tumor comparing to normal tissue enhances antitumor activity

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Abstract

To quantitatively evaluate the extravasation, accumulation and selectivity to tumor tissues of liposomal vincristine (LV), dorsal skin-fold window chambers on athymic mice with or without LX-1, a human small cell lung cancer, xenograft implants and fluorescent intravital microscopy imaging were used. In vitro studies show that minimal loss of fluorescence marker DiI from liposomes occurs after 4 days of inoculation in murine plasma, and the release profiles of DiI-LV and LV were essentially the same with approximately 40% of the encapsulated vincristine sulfate (VCR) released after 26 h. Significantly faster extravasation of DiI-LV from tumor vessels was shown compared to non-tumor tissue after single dose i.v. administration. The relative interstitial amounts at 60 min (RIA60) for tumor and non-tumor tissues were 0.837±0.314 and 0.012±0.091, respectively (P=0.01). DiI-LV accumulation was significantly higher in tumor than in normal tissue, which continued beyond 48 h. Both DiI-LV and LV showed significant antitumor effects in window chambers and in flank tumors, compared with controls and VLS alone. The preferential extravasation of DiI-LV from tumor vasculature as well as its differential retention in tumor tissue provides the basis for the enhancement in antitumor activity of LV over VCR.

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Acknowledgements

The authors thank Ms. Dai Wang for the help in image analysis.

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Authors and Affiliations

  1. Department of Radiation Oncology, Duke University Medical Center, 201 Med. Sci. Res. Bldg., Box 3455, Durham, NC, 27710, USA

    Siqing Shan, Cathy D. Peltz & Mark W. Dewhirst

  2. Department of Biomedical Engineering, Duke University, Durham, NC, 27710, USA

    Ave Krol & Fan Yuan

  3. Inex Pharmaceuticals Corporation, Glenyon Parkway, V5J 5J8, Burnaby, BC, Canada

    Clay Flowers, Heather Sweet, Norbert Maurer & Eun-Joo Gina Kwon

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  1. Siqing Shan
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  2. Clay Flowers
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  3. Cathy D. Peltz
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Correspondence to Mark W. Dewhirst.

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Shan, S., Flowers, C., Peltz, C.D. et al. Preferential extravasation and accumulation of liposomal vincristine in tumor comparing to normal tissue enhances antitumor activity. Cancer Chemother Pharmacol 58, 245–255 (2006). https://doi.org/10.1007/s00280-005-0145-x

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  • DOI: https://doi.org/10.1007/s00280-005-0145-x

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