Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome.
Liposomal drugs accumulate only in perivascular regions in tumors after i.v. injection. Thus, they cannot kill tumor cells in deeper tissue layers. To circumvent this problem, we investigated effects of doxorubicin (DOX) encapsulated in a lysolecithin-containing thermosensitive liposome (LTSL) on tumor microcirculation because damaging microvessels would stop nutrient supply to deeper tumor cells. We used LTSL-DOX in combination with hyperthermia to treat a human squamous carcinoma xenograft (FaDu) implanted in dorsal skinfold chambers in nude mice. Before the treatment, the RBC velocity in tumors was 0.428 +/- 0.037 mm/s and the microvascular density was 3.93 +/- 0.44 mm/mm(2). At 24 hours after the treatment, they were reduced to 0.003 +/- 0.003 mm/s and 0.86 +/- 0.27 mm/mm(2), respectively. The same treatment, however, caused only 32% decrease in the RBC velocity and no apparent change in microvascular networks in normal s.c. tissues over the same period. LTSL and LTSL-DOX alone had no effect on tumor microcirculation, and LTSL plus hyperthermia caused only a transient decrease in the RBC velocity in tumors. At 24 hours after treatments, tumor microcirculation in all these control experiments was insignificantly different from that before the treatments. We also examined apoptosis of cells in tumors at different time points after LTSL-DOX plus hyperthermia treatment and observed few apoptotic cells in tumor microvessels. In conclusion, the rapid release of DOX during hyperthermia could make the drug to shutdown tumor blood flow while have only minor effects on normal microcirculation in s.c. tissues.
Department of Biomedical Engineering, Duke University, Box 90281, Durham, NC 27708, USA.
Qing
Q
Chen
Sheng
S
Tong
Mark W
MW
Dewhirst
Fan
F
Yuan
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D001835:Body Weight; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000628:therapy*; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008081:Liposomes; D008244:Lysophosphatidylcholines; D004317:Doxorubicin