Abstract

Ovarian cancer is considered a major health problem. The chemotherapeutic
drugs that are used often are inadequate due to the development of drug
resistance. The evasion of apoptosis due to overexpression of anti-apoptotic
BCL-2 family members is a prominent cause of this resistance. These proteins are
also responsible for the progression of the disease. Navitoclax is a BH3
mimetic which inhibits several Bcl-2 family proteins including BCL- X_L,
as well as BCL-2. We have previously shown navitoclax potentiates cell death
induced by carboplatin. However, clinical success with navitoclax has been
limited because it causes mechanism-dependant thrombocytopenia through the
inhibition of BCL- X_L in platelets. Unfortunately, ovarian cancer is
particularly dependant on Bcl-X_L suggesting that strategies to
target navitoclax to ovarian cancer cells may be helpful. Here we have
investigated the formulation of navitoclax in nanoparticles to achieve this.

Navitoclax was encapsulated in nanoparticles comprising a poly(allylamine)-cholesteryl
(PAA-Ch₅) micellar core. The nanoparticles provided a 100-fold
improvement in the original navitoclax aqueous solubility. Navitoclax (2.5
µM) as a free drug elicited (27 ±8) % death of Ovcar-8 cells and (20 ± 3) %
death of Ovsaho cells compared with  (49
± 8)% and (47 ± 8)% cellular death caused by a similar concentration of
navitoclax in the nanoparticles, respectively. Carboplatin (13 µM) caused the
death of 28 ± 6% of Ovcar-8 cells and this was augmented by combination with
either free navitoclax (1 µM; 62 ± 5% cell death) or by a similar concentration
of navitoclax encapsulated in nanoparticles (69 ± 5% cell death). Neither
navitoclax (1 µM) nor nanoparticular navitoclax, nor the empty nanoparticles
elicited significant cell death. Similar results were observed with Ovsaho
cells. These results demonstrate that navitoclax can be effectively
encapsulated in nanoparticles and retains its ability to potentiate the
cytotoxic activity of carboplatin.