文摘
Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase鈥搒olubility analysis suggested that Red-Br-Nos complexed with 尾-CD and methyl-尾-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 脳 103 M鈥? and 4.27 脳 103 M鈥?. Fourier transforms infrared spectroscopy indicated entrance of an O鈥揅H2 or OCH3鈥揅6H4鈥揙CH3 moiety of Red-Br-Nos in the 尾-CD or methyl-尾-CD cavity. Furthermore, the cage complex of Red-Br-Nos with 尾-CD and methyl-尾-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH3鈥揅6H4鈥揙CH3 moiety was closer to the H5 proton of 尾-CD and the H3 proton of the methyl-尾-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH 鈭?7.4) was improved by 鈭?0.7-fold and 鈭?1.2-fold when mixed with 尾-CD and methyl-尾-CD, respectively. This increase in solubility led to a favorable decline in the IC50 by 鈭?-fold and 鈭?-fold for Red-Br-Nos鈭捨?CD-GGM and Red-Br-Nos鈥搈ethyl-尾-CD-GGM formulations respectively, compared to free Red-Br-Nos鈭捨?CD and Red-Br-Nos鈥搈ethyl-尾-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer.
Keywords:
Red-Br-Nos; colon cancer; 尾-cyclodextrin (尾-CD); methyl-尾-cyclodextrin (methyl-尾-CD); guar gum microspheres (GGMs); cytotoxicity
