Delivery of Antitumor Drug to Bladder Cancer by Use of Phase Transition Liposomes and Hyperthermia

Abstract

It has been proposed that liposomes (phospholipid bilayer vesicles) could be used to entrap enzymes or drugs and then be administered intravenously to patients as a natural molecule to be metabolized. After liposome degradation, the entrapped molecules would be released at higher concentrations in target tissues. In 1979, it was shown that liposomes containing a chemotherapeutic agent could preferentially release the agent at the transition temperature of the lipids. In an effort to deliver high dose methotrexate (MTX) to animal transitional cell carcinomas (TCC), we used liposomes with phase transition temperature a few degrees above 37C. Experimentally induced bladder TCC tumors (induced with N-(4-(5-nitro-2-furyl)-2 thiazolyl) formamide) were transplanted into hind legs of C3H/Bi mice. These animals received tritiated MTX encapsulated in phase transition liposomes. Tumors were heated to 42 ± 0.5C (by ultrasound) before receiving the liposomes containing tritiated molecules of MTX. After an appropriate time sequence the tumors were removed and MTX uptake of each tumor was noted and compared to the controls having unheated tumors. Heated TCC tumors accumulated 11.9-fold more MTX than nonheated tumors receiving the same dose. Animals receiving free MTX did not exhibit a temperature dependent difference. This indicates that the phase transition temperature of specifically engineered liposomes may be used to increase delivery of high dose methotrexate to transitional cell carcinomas.