Liposome-based drug delivery using secretory phospholipase A2 as a tumor-specific release mechanism: preclinical evaluation of efficacy, pharmacokinetics, and individual patient expression profiles

B24

The selectivity of anticancer drugs in targeting the tumor tissue presents a major problem in cancer treatment. Upon administration only a very limited fraction of a chemotherapeutic agent is getting access to the cancerous tissue, while the remaining fraction may lead to unwanted toxic side-effects in the healthy tissues. Liposome-based drug delivery has been thought to circumvent these problems, but so far only limited therapeutic improvements have been demonstrated, due to low drug leakage from the liposomes in the tumor.We have developed a new generation of liposomes, called LiPlasomes, which are specifically designed to be susceptible to degradation by the enzyme, secretory phospholipase A2 type IIA (sPLA2). High expression of sPLA2 has been reported in a number of solid tumors. In contrast to normal tissue, tumor vessels are relatively porous allowing LiPlasomes to extravasate into the tumor. The enhanced permeability and retention effect will subsequently ensure persistently high concentrations of the LiPlasomes in the extracellular space surrounding the tumor cells. We hypothesize that the high level of sPLA2 in the tumor cells will cause specific and efficient degradation of the LiPlasomes resulting in release of its interior and, in addition, production of free fatty acids and lysolipids. These hydrolysis products can act as locally released membrane permeability enhancers promoting transmembrane uptake of the released anticancer agent into the cytoplasm of the tumor cells.In vitro experiments comparing LiPlasomes containing cisplatin (named LiPlacis) and free cisplatin have shown sPLA2-dependent, efficient and synergistic inhibition of growth and cell death using MTT- and clonogenic assays on various tumor cell lines. In addition, the pharmacokinetic behavior of the LiPlacis formulation has been studied upon intravenous administration in rats. Compared to free cisplatin, LiPlacis was found superior judged by various pharmacokinetic parameters such as half-time, total drug exposure over time (AUC) and volume-of-distribution. In vivo efficacy studies on nude mice carrying xenografted tumors further confirmed the more efficient effect of LiPlacis-encapsulated cisplatin compared to free cisplatin. As the presence of sPLA2 in the tumor microenvironment is of crucial importance for the LiPlasome strategy, we have performed immunohistochemistry to determine the expression of sPLA2 in a number of primary, solid tumors (i.e. in prostate, testis, esophagus, colo-rectum, mamma) and found significant, but varying expression of sPLA2.Overall, these data demonstrate that the use of sPLA2 as a tumor-specific release mechanism is a promising approach for optimizing future cancer treatment. We are currently evaluating suitable animal models for further testing of the in vivo behavior of LiPlasomes.