In Vitro Cytotoxicity and In Vivo Antitumor Efficacy of Tetrazolato-Bridged Dinuclear Platinum(II) Complexes with a Bulky Substituent at Tetrazole C5

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)(2)}(2)(mu-OH)(mu-5-R-tetrazolato-N2,N3)](2+); tetrazolato-bridged complexes) are a promising source of next-generation platinum-based drugs. beta-Cyclodextrin (beta-CD) forms inclusion complexes with bulky organic compounds or substituents, changing their polarity and molecular dimensions. Here, we determined by H-1-NMR spectroscopy, the stability constants for inclusion complexes formed between beta-CD and tetrazolato-bridged complexes with a bulky, lipophilic substituent at tetrazole C5 (complexes 1-3, phenyl, n-nonyl, and adamantyl substitution, respectively). We then determined the in vitro cytotoxicity and in vivo antitumor efficacy of complexes 1-3 against the Colon-26 colorectal cancer cell line in the absence or presence of equimolar beta-CD. Compared with the platinum-based anticancer drug oxaliplatin (1R,2R-diaminocyclohexane)oxalatoplatinum(II)), complex 2 had similar cytotoxicity, complex 3 was moderately cytotoxic, and complex 1 was the least cytotoxic. The cytotoxicity of the complexes decreased in the presence of beta-CD. When we examined the in vivo antitumor efficacy of complexes 1-3 (10 mg/kg) against homografted Colon-26 colorectal tumors in male BALB/c mice, they showed a relatively low tumor growth inhibition compared with oxaliplatin. However, in the presence of beta-CD, complex 3 had higher in vivo antitumor efficacy than oxaliplatin, suggesting a new direction for future research into tetrazolato-bridged complexes with high in vivo antitumor activity.