Myrra G. Carstens

Recognition and clearance of methoxypoly (ethyleneglycol) 2000-grafted liposomes by macrophages with enhanced phagocytic capacity. Implications in experimental and clinical oncology

Intravenous injection of an endotoxin-free solution of poloxamine-908 to rats can enhance the phagocytic clearance capacity of tissue macrophages, particularly those of the liver and the spleen. Such stimulated cells were able to clear a significant portion of intravenously injected methoxypoly(ethyleneglycol)2000 liposomes (mean size of 87 nm), labelled with technetium-99m via the N-hydroxysuccinimidyl hydrazine nicotinate hydrochloride derivative of distearoyl phosphatidylethanolamine, within 4 h post administration. These liposomes, otherwise, exhibit long circulatory behaviour in control animals, with poor localization to the liver and spleen. We suggest that such technetium-99m-labelled engineered vesicles may be of aid for detection of the liver and spleen macrophages with enhanced phagocytic clearance capacity by gamma scintigraphy. Alterations in the phagocytic activity of liver and spleen macrophages is known to occur during cancer. Therefore, such diagnostic procedures may prove useful for patient selection or for monitoring the progress of treatment with long circulating nanoparticles carrying anti-cancer agents, thus minimizing damage to this important line of bodys defence cells, and are discussed.

Pharmaceutical Micelles: Combining Longevity, Stability, and Stimuli Sensitivity

Targeted drug delivery is of particular importance for the treatment of life-threatening diseases such as cancer, since the adverse effects of cytostatic drugs can be very detrimental (Crommelin et al., 1995; Gros et al., 1981; Moses et al., 2003). Nowadays, polymer micelles are extensively studied as drug delivery systems to fulfill the requirements for selective and tissue-specific drug delivery (Adams et al., 2003; Allen et al., 1999; Gaucher et al., 2005; Jones and Leroux, 1999; Kabanov et al., 1992; Kataoka et al., 2001; Kreuter, 2006; Kwon, 2003; Lavasanifar et al., 2002b; Liu et al., 2007; Moghimi et al., 2001; Nishiyama and Kataoka, 2006; Torchilin, 2001, 2006; Yokoyama et al., 1992). The most attractive feature is their hydrophobic core with a relatively large capacity to accommodate hydrophobic agents, which are normally difficult to formulate. Polymeric micelles have been used to encapsulate a great variety of highly potent but hydrophobic drugs (Avgoustakis et al., 2002; Cheng et al., 2007; Djordjevic et al., 2005; Lee et al., 2007; Lin et al., 2003, 2005; Nishiyama et al., 2001, 2003; Yi et al., 2005; Yokoyama et al., 1998; Zamboni, 2005), such as doxorubicin (DOX) (Gillies and Frechet, 2005; Hruby et al., 2005; Kabanov et al., 2002b; Lee et al., 2005; Nakanishi et al., 2001; Rapoport, 2004; Yokoyama et al., 1992), paclitaxel (PTX) (Cavallaro et al., 2003; Hamaguchi et al., 2005; Huh et al., 2005; Kim et al., 2001, 2004; Krishnadas et al., 2003; Liggins and Burt, 2002; Shuai et al., 2004; Torchilin et al., 2003;), amphotericin B (Lavasanifar et al., 2002), and photosensitizers used for the treatment of cancer (Le Garrec et al., 2004; van Nostrum, 2004; Zhang et al., 2003). Some of these micellar formulations have already entered clinical trials and showed promising results with regard to their therapeutic index in cancer patients (Barratt, 2000; Kim et al., 2004; Matsumura et al., 2004; Torchilin, 2006). A drug delivery system needs to fulfill several (pharmaceutical) requirements such as a significant increase in therapeutic effect with respect to the free drug, good biocompatibility, and the possibility to scale-up the production of the micellar formulation. In addition, the ideal micellar system (1) has long circulating properties and adequate stability in the blood stream, (2) has a high drug-loading capacity, (3) is able to selectively accumulate at the target site, and (4) offers the possibility to control the release of Pharmaceutical Micelles: Combining Longevity, Stability, and Stimuli Sensitivity