Inclusion complex of a Bcl-2 inhibitor with cyclodextrin: characterization, cellular accumulation, and in vivo antitumor activity.

Small molecule inhibitors always exhibit poor water solubility due to the inherent hydrophobic property. It is an important challenge when they are developed as a real drug. S1, a structure-specific Bcl-2 inhibitor encountered this issue when moved forward in preclinical development. Herein, we prepared a 1:1 type of S1-gamma-cyclodextrin (S1-gamma-CD) inclusion complex to enhance the solubility. Bioevaluation of this new formulation was carried out totally in water solution. The cell internalization and cellular accumulation of S1-gamma-CD was illustrated by its fluorescence analogue S2. Disruption of Bcl-2/Bax heterodimerization in MCF-7 cells further revealed S1-gamma-CD could reach the subcellular function site. Moreover, the even stronger disruption by S1-gamma-CD than free S1 was found due to the higher local concentrations. Furthermore, the in vivo antitumor activity of S1-gamma-CD was evaluated in the H22 xenograft model. Results showed it exhibited significant antitumor activity with a decrease of tumor size (average tumor volume = 234 +/- 76 mm(3) vs control group, 398 +/- 121 mm(3), P < 0.01, and S1 group, 296 +/- 65 mm(3), P < 0.05), and a much longer survival time (the median time to the end point = 39.9 days vs control group, 29.2 days, P < 0.01). More importantly, the similar disruption of Bcl-2/Bax was found in S1-gamma-CD treated mice and free S1 treated ones. It demonstrated that S1-gamma-CD not only obtains a pharmaceutical level in vivo but also maintains the mechanism-based antitumor ability of S1 itself. It has been identified that cyclodextrin is appropriate to deliver a structure-specific molecule to its subcellular function site without any adverse effects on its mechanism-based potency, in either cultured cells or animals.