title: Preferential extravasation and accumulation of liposomal vincristine in tumor comparing to normal tissue enhances antitumor activity.
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 (RIA(60)) 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.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Shan
authors.forename: Clay
authors.initials: C
authors.lastname: Flowers
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Peltz
authors.forename: Heather
authors.initials: H
authors.lastname: Sweet
authors.forename: Norbert
authors.initials: N
authors.lastname: Maurer
authors.forename: Eun-Joo Gina
authors.initials: EJ
authors.lastname: Kwon
authors.forename: Ave
authors.initials: A
authors.lastname: Krol
authors.forename: Fan
authors.initials: F
authors.lastname: Yuan
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005456:Fluorescent Dyes; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014018:Tissue Distribution; D014750:Vincristine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D008081:Liposomes; D014750:Vincristine