Use of nanoparticles to improve the therapeutic index of navitoclax

Abstract

Ovarian cancer is considered a major health problem in women. The chemotherapeutic drugs that are used often are inadequate due to the development of drug resistance. This s related to many causes, and one of them is an evasion of apoptosis. One of the major causes that stand behind this apoptosis escaping is overexpression of anti-apoptotic BCL-2 family members. Thus, this encouraged the researchers to think about new solutions for the treatment of ovarian cancer. One of these solutions was the development of BH3 mimetics, which are small molecules inhibitors of anti apoptotic BCL-2 family members and have the capability to cause an apoptosis in the ovarian cancer cells. Furthermore, they increase the ovarian cancer cells sensitivity to chemotherapeutic agents. Navitoclax (ABT-263) belongs to this family and has the advantage of inhibition of BCL-XL, as well as BCL-2. Studies showed that inhibition of BCL-XL leads to ovarian cancer regression in xenografts in mice. However, clinical investigations have been restricted because of a major side effect that navitoclax causes, which is thrombocytopenia. Thus, this led to think about new strategies to broaden its therapeutic window and formulation of navitoclax as nanoparticles is one of these strategies. This novel formulation is composed of navitoclax in addition to comb-shaped polymer (poly(allylamine) (PAA) derivatives). This polymeric backbone was modified with cholesteryl moieties (PAA-ch5), which showed improvement in the solubilisation of several hydrophobic drugs. The specific phenomenon of nanoparticles is that they can accumulate preferentially in tumours by enhanced permeability and retention effect (EPR). Accordingly, this can lead to target navitoclax passively toward ovarian cancer cells and avoid platelets accumulation. Furthermore, this targeting can be more enhanced by attaching nanoparticles with folate moiety because folate receptors are known to be over-expressed on ovarian cancer cells as well as other cancers.