Carrier-mediated and artificial-cell targeted cancer drug delivery - Artificial Cells, Cell Engineering and Therapy - page 491

liposomes enter tissue and tumors, and release drug are not completely
understood. In addition, the liposomes can be engineered to produce a complete
spectrum of drug release rates which need to be evaluated in in vivo systems.
SPI-077 (ALZA Pharmaceuticals, Inc.) is cisplatin encapsulated in long-
circulating Stealth Õ liposome. The disposition of liposomal-cisplatin is dependent
on the liposomal vehicle (De Mario et al., 1998; Harrington et al., 2001a; Veal et
al., 2001). Once the cisplatin is released from the liposome, its disposition follows
cisplatin pharmacology. SPI-077 has shown antitumor activity against a wide
range of solid tumor xenografts, including murine colon tumors. In a study
comparing SPI-077 and cisplatin tumor disposition in mice bearing murine colon
tumors, the platinum exposure was several fold higher and prolonged after SPI-
077 as compared with cisplatin administration (Newman et al., 1999). However,
because the platinum exposure was measured in tumor extracts, it is unclear
whether the platinum measured was encapsulated, protein-bound platinum or
unbound-platinum. In addition, it is unclear whether the platinum exposure was
intracellular or extracellular. Thus, it is currently unclear whether SPI-077
releases cisplatin into the tumor extracellular fluid (ECF), or penetrates into the
cell as the liposome and then releases the cisplatin intracellularly.
Thus, the tumor disposition of platinum after administration of liposomal
formulations of cisplatin (SPI-077) and non-liposomal cisplatin was evaluated
using microdialysis in mice bearing B16 murine melanoma tumors (Thompson
et al., 2001). Owing to the pore cut-off size (20 kDa) of the semipermeable
membrane of the microdialysis probe and the size of the liposome (100 nm), the
microdialysis probe was only be able to sample unbound-platinum and allow the
differentiation between liposomal-encapsulated cisplatin and cisplatin released
into the tumor ECF.
After administration of cisplatin, the concentration of unbound-platinum in
tumor ECF was detectable from 12 to 120 min after administration. However,
there was no detectable unbound-platinum in the tumor ECF after administration
of SPI-077. The total-platinum in tumor extracts, unbound-platinum in tumor
ECF as measured by AUC, and formation of Pt-GG DNA adducts after
administration of cisplatin and SPI-077 are presented in Fig. 21.6 (Pluim et al.,
1999). The results of this study suggest SPI-077 distributes into tumors, but
release significantly less platinum into tumor ECF which results in lower
formation of Pt-DNA adducts compared with cisplatin. This was the first study
using microdialysis methodology to evaluate the tumor disposition of liposomal
encapsulated anticancer agents.
21.4 Conclusions
Liposomes and nanoparticles may be an effective carriers to deliver anticancer
agents to tumors (Allen and Hansen, 1991; Allen and Stuart, 2005; Drummond
et al., 1999; Papahadjopoulos et al., 1991; Zamboni et al., 2004; D'Emanuele