title: Inclusion complex of a Bcl-2 inhibitor with cyclodextrin: characterization, cellular accumulation, and in vivo antitumor activity.
abstract: 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.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China. zczhang@dlut.edu.cn
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Guiye
authors.initials: G
authors.lastname: Wu
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.forename: Ting
authors.initials: T
authors.lastname: Song
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D047408:gamma-Cyclodextrins / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D047408:gamma-Cyclodextrins; C023792:gamma-cyclodextrin