Carrier-mediated and artificial-cell targeted cancer drug delivery - Artificial Cells, Cell Engineering and Therapy - page 471

and retention effect (Maeda et al., 2000). Pegylated-Stealth TM liposomal
doxorubicin (Doxil Õ , Caelyx Õ ) and paclitaxel albumin-bound particles
(Gradishar, 2006; Socinski, 2006) are the only two members of this relatively
new class of agents that are FDA approved (Krown et al., 2004; Markman et al.,
2004; Socinski, 2006). Doxil is approved for the treatment of refractory ovarian
cancer and Kaposi's sarcoma (KS) (Krown et al., 2004; Markman et al., 2004;
Rose, 2005). Non-pegylated liposomal formulations of doxorubicin, Myocet Õ
and DaunoXome Õ are approved in Europe for the treatment of breast cancer
and KS, respectively (Allen and Martin, 2004). Abraxane is approved for the
treatment of refractory breast cancer. However, there are more than 50 other
agents that are in preclinical and clinical development. Newer generations of
liposomes containing two anticancer agents with a single liposome and
antibody-targeted liposomes which may improve selective toxicity are in
preclinical development (Abraham et al., 2004; Laginha et al., 2005; Park et al.,
2004). In addition, nanoparticle formulations, such as microspheres, dendrimers
and conjugates provide a unique method to provide tumor-selective delivery of
anticancer agents to tumors. As more existing anticancer agents go off patent
these agents will be most likely be evaluated in some type of liposome or
carrier-mediated formulation. In addition, anti-angiogenesis agents, antisense
oligonucleotides and enzymes represent rational candidates for liposomal and
nanoparticle formulations (Park et al., 2004).
The pharmacokinetic disposition of these agents is dependent upon the carrier
and not the parent-drug until the drug is released from the carrier (Laginha et al.,
2005). Thus, the pharmacology and pharmacokinetics of these agents are
complex and detailed studies must be performed to evaluate the disposition of
the encapsulated or conjugated form of the drug and the released active-drug
(Zamboni et al., 2004). The factors affecting the pharmacokinetic and
pharmacodynamic variability of these agents remain unclear, but probably
include the reticuloendothelial system (RES), which has also been called the
mononuclear phagocyte system (MPS) (Laverman et al., 2001; Litzinger et al.,
1994; Woodle and Lasic, 1992).
21.1.3 Methods for evaluation of carrier agents
The need to develop and readily gain information on the tumor disposition of
agents may become more important with the increasing number of tumor
targeting approaches, such as gene and antisense therapy, polyethylene glycol
(PEG)-conjugated agents and liposomal delivery (Brunner and Muller, 2002;
Zamboni et al., 2004). In addition, methodology and study designs used to
develop classic cytotoxic anticancer agents, such as platinum, taxane and
camptothecin analogs, may not be appropriate for the new generations of
anticancer therapy, such as angiogenesis inhibitors, antiproliferative agents and
signal transduction inhibitors (Brunner and Muller, 2002; Gelmon et al., 1999).