Antitumor Activity of 5'-O-Dipalmitoylphosphatidyl 2'-C-Cyano-2'-deoxy-1-.BETA.-D-arabino-pentofuranosylcytosine Is Enhanced by Long-Circulating Liposomalization.

Abstract

We previously synthesized the 5'-O-diacylphosphatidyl derivative of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC), a novel antitumor nucleoside, and observed it to have a high antitumor activity. Since this compound is readily incorporated into liposomal membranes, we liposomalized the compound using a formulation for conventional and long-circulating liposomes, and investigated the antitumor activity of liposomal 5'-O-dipalmitoylphosphatidyl CNDAC (DPP-CNDAC). Long-circulating liposomes composed of DPP-CNDAC, dipalmitoylphosphatidylcholine, cholesterol and palmityl-D-glucuronide (PGlcUA) (2:2:2:1 as a molar ratio), as well as liposomes containing dipalmitoylphosphatidylglycerol (DPPG) instead of palmityl-D-glucuronide and those composed of only DPP-CNDAC, were injected intravenously into Meth A sarcoma-bearing mice. DPP-CNDAC showed suppression of tumor growth, whereas CNDAC did not at the same concentration, suggesting that 5'-phosphatidylation is useful to enhance therapeutic efficacy. Furthermore, liposomal DPP-CNDAC reduced the acute toxicity, and liposomes containing PGlcUA showed more enhanced activities of reducing tumor growth and increasing the lifetime of the mice than liposomes containing DPPG. To obtain a higher therapeutic efficacy, we injected long-circulating liposomal DPP-CNDAC 5 times. The tumor growth was suppressed to 13.2% (86.8% inhibition), and the survival time of the tumor-bearing mice increased to 128.5% with one completely cured mouse out of five. Next, the effect of DPP-CNDAC incorporation on the in vivo behavior of PGlcUA and DPPG liposomes was examined by a non-invasive method using positron emission tomography (PET). Liposomes were labeled with [2-(18)F]-2-fluoro-2-deoxy-D-glucose, and administered to tumor-bearing mice. PET images and time-activity curves indicated that DPP-CNDAC/PGlcUA-liposomes tended to accumulate in tumor tissues a little bit more than DPP-CNDAC/DPPG-liposomes, although the difference between the two kinds of liposomal distribution was not as marked as between PGlcUA and DPPG liposomes, suggesting that DPP-CNDAC incorporation partly affected the liposomal behavior in vivo but that the long-circulating character of PGlcUA-liposomes might not be fully abolished. Thus, the enhanced therapeutic efficacy of long circulating liposomalized DPP-CNDAC observed here may be due to passive targeting of DPP-CNDAC to the tumor tissue, making this formulation of DPP-CNDAC useful for cancer chemotherapy.

Cancer Anti-angiogenic Therapy

“…65) In fact, liposomalization of an anti-cancer agent enhanced the anticancer effect because of longcirculation in the bloodstream and the subsequent accumulation in tumor tissue due to enhanced permeability and retention (EPR) effect. [66][67][68][69] Furthermore, angiogenic endothelial cells are believed to express several specific molecules, which are known or unknown, in comparison with normal endothelial cells. Therefore, these distinct marker molecules may provide active targeting guides for anti-neovascular therapy.…”

Anti-neovascular therapy using novel peptides homing to angiogenic vessels

“…Then, liposomal traf- ®cking in tumor bearing mice was analysed by PET as described previously (Asai et al, 1998;Oku, 1999b). In brief, Colon 26 NL-17 bearing Balb/c mice were anesthetized and injected via a tail vein with 18 F-labeled liposomes.…”

“…Newly formed blood vessels have the characteristics of high permeability induced by vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), and macromolecules such as liposomes are known to passively accumulate in tumor tissues as a re¯ection of the feature (Asai et al, 1998;Oku, 1999a). On the other hand, angiogenesis consists of a complex process involving the recruitment of endothelial progenitor cells (Asahara et al, 1997(Asahara et al, , 1999Ito et al, 1999), as well as proliferation, migration and capillary formation by activated-endothelial cells.…”

Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

“…5 An alternative approach to delivering MMC via longcirculating liposomes was to design a lipophilic prodrug that would be retained in liposomes, but could gradually release active MMC upon exposure to appropriate environmental conditions. Attachment of drugs to bilayer-compatible lipids can ensure prolonged association with a liposome (18,19), where an acceptable release rate is determined by the proper choice of the linkage. We have prepared a lipophilic MMC prodrug conjugate where the drug is attached to 1,2-distearoyl glycerol lipid via a cleavable dithiobenzyl linker ( Fig.…”