Tumor microvascular permeability is a key determinant for antivascular  effects of doxorubicin encapsulated in a temperature sensitive   liposome.
Previous data have demonstrated that doxorubicin (DOX) released from a lysolecithin-containing thermosensitive liposome (LTSL) can shut down blood flow in a human tumor xenograft (FaDu) in mice when the treatment is combined with hyperthermia (HT), suggesting that LTSL-DOX is a potential antivascular agent. To further understand mechanisms of the treatment, we investigated effects of LTSL-DOX (5 mg/kg body weight) plus HT (42 degrees C, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers and dose responses of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT. We observed that LTSL-DOXHT could significantly reduce blood flow and microvascular density in 4T07 tumors. The antivascular efficacy of LTSLDOX- HT could be enhanced through increasing tumor microvascular permeability of liposomes by using platelet activating factor (PAF). We also observed that the dose responses of FaDu and 4T07 to DOX in vitro were similar to each other and could be enhanced by HT. Taken together, these data suggested that tumor microvascular permeability was more critical than the sensitivity of tumor cells to DOX in determining the antivascular efficacy of LTSL-DOX-HT treatment.
Chen
Qing
Q
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
Krol
Ava
A
Wright
Alex
A
Needham
David
D
Dewhirst
Mark W
MW
Yuan
Fan
F
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001783:Blood Flow Velocity; D002199:Capillary Permeability; D004317:Doxorubicin / Q000627:therapeutic use*; D004337:Drug Carriers; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008081:Liposomes / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013696:Temperature
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin