PARENT SESSION
2:30 PM to 3:30 PM
Monday, April 22, 2002
Poster Session 5 Heat Combined with Drugs
Room: Nevada 4-5
(MP05-44) Potentiation of immunoliposome-mediated drug delivery to tumors by local hyperthermia.
Kirpotin, Dmitri*,1,2, Park, John2, Stauffer, Paul2, Shao, Yi1, Diederich, Chris2, Marks, James2, Benz, Christopher3, Hong, Keelung1, 1 California Pacific Medical Center Research Institute, San Francisco, CA2 University of California San Francisco, San Francisco, CA3 Buck Institute for Age Research, Novato, CA
ABSTRACT-
Drug delivery to cancer cells by antibody-conjugated immunoliposomes (ILS) is an emerging modality in cancer chemotherapy. Local hyperthermia (HT) has been shown to increase the tumor uptake of liposomes. We studied the effect of HT on the tumor uptake and antitumor efficacy of ILS-encapsulated doxorubicin in an animal model. Doxorubicin encapsulated into ILS targeted to ErbB2 oncoprotein (ILS-DOX) was prepared from a commercial liposomal doxorubicin (Doxil, Alza Corp.; LS-DOX) by incubation with a highly internalizable anti-ErbB2 scFv (F5) conjugated to poly(ethylene glycol)-lipid (30 scFv/liposome). Tumor uptake studies used liposomes containing 67Ga-DTPA instead of the drug. Human breast cancer xenografts (200-400 cu. mm) were raised s.c. in nude mice using cell lines with high ErbB2 (BT-474; 600,000 copies/cell) or low ErbB2 (MCF-7, 10,000 copies/cell). HT (42.2-42.7 deg.C; thermocouple array) was applied to tumors by 3 MHz ultrasound (US ) via contact water bath for 30-60 min. Normothermic controls were similarly treated without US power. Liposomal doxorubicin or saline control were given i.v. as a single dose of 5 mg/kg 30 min before or after HT, with the same results. Tumors were measured by caliper for 45 days post treatment . Average tumor doubling time (ADT) per study arm (7-10 animals) was determined using mono-exponential model. Without antibody-directed targeting, HT increased the tumor uptake of liposomes 2.5-3 times over normothermic controls. With targeting, the uptake of ILS by HT-treated tumors increased 6-fold. Without HT, antibody-directed targeting did not increase tumor uptake of the liposomes. HT, LS-DOX, and ILS-DOX increased ADT of BT-474 tumors from 26.7 days (control) to 68 days, 54 days, and 142 days, respectively; HT+LS-DOX increased ADT to 250 days, but only HT+ILS-DOX lead to tumor regression (average time to 50% regression, 41 day), with 6 of 7 animals having regressing tumors. Thus, HT increases the intratumoral pool of immunoliposomes and leads to better anti-tumor efficacy of immunoliposome-encapsulated drug.
KEYWORDS: Hyperthermia, Liposomes, Antibodies, Drug targeting