LONG-CIRCULATING LIPOSOMES FOR DRUG-DELIVERY IN CANCER-THERAPY - A REVIEW OF BIODISTRIBUTION STUDIES IN TUMOR-BEARING ANIMALS

Inhibition of the rapid uptake of liposomes by the reticulo-endothelia l system (RES) and reduction of the rate of drug leakage have resulted in long-circulating liposomal drug systems with valuable pharmacologi c properties. Particularly, the coating of liposomes with polyethylene -glycol (PEG) confers optimal protection to the vesicles from RES-medi ated clearance, while bilayer rigidification using high T-m phospholip ids reduces the rate of leakage of liposome contents. These carrier sy stems display an improved extravasation profile with enhanced localiza tion in tumors and possibly in other tissues, such as skin. An anti-ca ncer drug, doxorubicin, encapsulated in small-sized (<100 nm diameter) , PEG-coated liposomes with a rigid bilayer shows a unique pharmacokin etic pattern, characterized by extremely long half-life, slow clearanc e, and small volume of distribution. Liposome longevity in circulation correlates positively with high drug levels in the extracellular tumo r fluid and with enhanced therapeutic efficacy in a variety of tumor m odels regardless of the site of tumor growth. Examples of biodistribut ion studies will be presented for several murine tumors and human tumo r xenografts inoculated by various routes, including a brain-implanted tumor. Liposome localization in tumors appears to be the result of an enhanced rate of extravasation through the abnormally permeable micro vasculature of tumors coupled with an impaired lymphatic drainage. The se results stress the potential of these long-circulating liposomal sy stems to manipulate the pharmacokinetics of anticancer drugs and enhan ce drug delivery to tumors. This therapeutic approach has been validat ed in AIDS-related Kaposi's sarcoma and is now undergoing extensive cl inical testing in solid tumors.