Gelatinase targeted peptidoliposomes suppress the growth of human ovarian tumor xenografts in nude mice

4586 A specific peptide inhibitor CTTHWGFTLC (CTT1) of gelatinases (MMP-2 and MMP-9) has been isolated from phage display peptide libraries (Koivunen et al . 1999, Nature Biotechnology 17, 768-774). This cyclic decapeptide was shown to prevent tumor growth and to improve survival of nude mice bearing human tumors. We have designed a more hydrophilic derivative of CTT1-peptide. Here, we have studied the pharmacokinetics of this novel CTT2-peptide and shown that CTT2 exhibits lower liver accumulation than the original phage display derived peptide. CTT2 accumulation was then screened in 12 different gelatinase expressing human xenograft tumors. High accumulation of CTT2 was seen in ovarian xenografts, and the highest accumulation was observed in serous type ovarian carcinoma where tumor/muscle ratio was 35 at 180 min after peptide injection. The peptide did not accumulate significantly in any other tissues studied. To generate tumor targeted liposomes (CTT2-SL), the CTT2-peptide was coupled covalently on the surface of doxorubicin loaded liposomes (SL). After single i.v. dose the CTT2-SL showed pharmacokinetics that were indistinguishable from that of SL in xenograft mice. Furthermore, CTT2-SL retains non-immunogenicity of SL. A biodistribution study showed that tumor AUC of doxorubicin encapsulated inside CTT2-SL is 40% greater than that of doxorubicin encapsulated inside SL. Finally, therapeutic efficacy of CTT2-SL was compared to that of SL. Mice were inoculated with ovarian carcinoma cells that were shown to be sensitive to doxorubicin in in vitro assay. Afterwards, the mice were treated systemically three times in three day intervals with CTT2-SL or SL (9mg/kg doxorubicin equivalents). The life span of mice treated with CTT2-SL increased 35% when compared to SL treated mice. We conclude that CTT-liposomes represent a promising technology to treat gelatinase expressing solid tumors. Based on these results, the development of CTT-SL peptidoliposomes toward clinical trials is underway.