However, pharmacokinetics of BPs require delivery method to escape bone and to target macrophages. Liposomes encapsulating CLO were successfully used to achieve temporary macrophage depletion in the spleen [21]. The authors

demonstrated that once phagocytosed, the liposomal membranes were disrupted by the phospholipases of the lysosomes, and the drug is released into the cell. Other studies Inhibitors,research,lifescience,medical confirmed macrophage elimination from the spleen, following intravenous (i.v.) injection of CLO entrapped into liposome by the absence of lysosomal acid phosphatase activity [21, 22] and surface markers of macrophages [23] as well as by the absence of cells with the MAPK inhibitor capacity to Inhibitors,research,lifescience,medical ingest and accumulate carbon particles from the circulation [22]. Ultrastructural studies also confirmed that macrophages not only lose some of their functional characteristics but are also physically removed from the circulation [26]. Growth inhibition of macrophages-like

cells by using liposomes encapsulating BP was also confirmed with other BPs, namely, PAM and ETI, on RAW 264 and CV1 cells [24]. In this study, free BPs were Inhibitors,research,lifescience,medical found to be even 1000 times less active, compared with the corresponding liposome-based formulations. Interestingly, the use of high calcium extracellular concentration resulted in a stronger macrophage depletion, suggesting the role of calcium to mediate BP cell uptake [24, 27]. The liposome Inhibitors,research,lifescience,medical type affected macrophage depletion, which was higher when using negatively charged unilamellar

liposomes [27]; however, this effect was found only in the case of CLO and ETI but not in the case of PAM. Finally, the use of calcium/bisphosphonate complex was found to lead to an enhanced uptake into cells but not to an inhibitory effect on the cytokine production by macrophages [27]. BP-encapsulating liposomes, when intravenously administered, led to elimination of macrophages from spleen and liver [25] but not those in other organs [23], reflecting the pharmacokinetics of the carrier. Accordingly, subcutaneous Inhibitors,research,lifescience,medical footpad administration of the BP-encapsulating liposomes resulted in macrophage elimination in draining lymph nodes [28] while intratracheal administration exclusively eliminates macrophages from lung tissues [29]. Liposome encapsulating BPs were used to enhance tumor growth in an experimental model of liver metastasis [30]. Rat inoculation with colon carcinoma unless cells resulted in a strong enhanced tumor growth in the liver only when the animals were pretreated with an i.v. injection of CLO-encapsulating liposomes. This effect was attributed to the effective elimination of all Kupffer cells that are preferential accumulation site for colloidal carriers. Accordingly, in the same experiment, nonphagocytic cells into the liver were not affected [30]. In contrast, liposome encapsulating CLO have been successfully used to inhibit the tumor growth.