Pharmacokinetic Properties and Applications of Drug Carriers

SM-liposomes described by Allen et al. dramatically reduced the uptake by the RES and exhibited a prolonged circulation in blood and, consequently, accumulated in tumor tissue.45 Gabizon and Papahadjopoulos53 have examined a number of other natural and synthetic lipids to prolong the circulation time and lead to preferential uptake by tumor cells in vivo. In these respects, SM-con-taining liposomes would be an attractive option as a tumor targeting carrier for highly lipophilic anti-tumor drugs. The preparation of SM containing emulsion formulations has been also described to prolong the blood retention of encapsulated [3H] labeled ATRA.54 Furthermore, after the intravenous injection of vincristine encapsulated in SM-liposomes, the plasma vincristine level was 7-fold higher than that following administration in the form of bare liposomes, and the half-life of the elimination from the circulation was prolonged.55,56 The improved circulation lifetime of vincristine in SM-liposomes correlated with the increased vincristine accumulation in subcutaneous solid A431 human xenograft tumors. Moreover, treatment with vincristine in SM-liposomes delayed the increase in tumor mass.55

PEG-liposomes are the most widely studied stealth liposomes. This occurs because the presence of PEG protects liposomes from the interaction with opsonins in the blood plasma and prevents their rapid uptake by the RES.46,57,58 Therefore, doxorubicin encapsulated into PEG liposomes exhibited a dramatically increase in circulating time in blood and much better therapeutic efficacy as compared with the free drug. Therefore, they are currently being used in the clinic as a component of Doxil®.59 On the other hand, as far as active targeting is concerned, galactose modification could be an attractive tool for PC targeting of lipophilic drugs. Recently, a novel galactosylated cholesterol derivative, Gal-C4-Chol, that could be stably incorporated into liposomes by means of its lipophilic anchor and allowed the introduction of galactose residues on the surface of the liposomes was synthesized.60,61 After intravenous injection, galactosylated liposomes prepared using Gal-C4-Chol were preferentially taken up by the liver.62 In addition, prostaglandin E63 and probucol64 were investigated as model lipophilic drugs incorporated in galactosylated liposomes prepared using Gal-C4-Chol, and they were found to be effectively taken up by PC. Recently, other types of galactosylated liposome were developed.65

Using a mannosylated cholesterol derivative (Man-C4-Chol) that was synthesized by the same method as Gal-C4-Chol, mannosylated liposomes (Man-liposomes) for non-parenchymal cell (NPC) and macrophages targeting were prepared.66-68 As far as cancer immunotherapy was concerned, macrophages, Kupffer cells, and dendric cells are attractive targets. These cells expressed a large number of mannose receptors on the cell surface and, therefore, Man-liposomes would be ideal carriers for cancer therapy. Previous studies have shown that Kupffer cells (contained in NPC) can be activated to a tumor reducible state by the administration of immunomodulators such as muramyl dipeptide.69 However, muramyl dipeptide parentally administrated in free form is rapidly cleared from the body and excreted in the urine.70 It was demonstrated that active targeting of muramyl dipeptide to liver non-parenchymal cells by Man-liposomes resulted in more effective inhibition of liver metastasis than delivery of muramyl dipeptide by liposomes without mannose.71 Moreover, treatment with muramyl dipeptide incorporated in Man-liposomes increased the survival of tumor-bearing mice.71

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