title: Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery.
abstract: 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-solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 10(3) M(-1) and 4.27 × 10(3) M(-1). Fourier transforms infrared spectroscopy indicated entrance of an O-CH₂ or OCH₃-C₆H₄-OCH₃ moiety of Red-Br-Nos in the β-CD or methyl-β-CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH₃-C₆H₄-OCH₃ moiety was closer to the H₅ proton of β-CD and the H₃ proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC₅₀ by ∼2-fold and ∼3-fold for Red-Br-Nos-β-CD-GGM and Red-Br-Nos-methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos-β-CD and Red-Br-Nos-methyl-β-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.
authors.affiliation: Department of Biology and §Department of Chemistry, Georgia State University , Atlanta, Georgia 30303, United States.
authors.forename: Jitender
authors.initials: J
authors.lastname: Madan
authors.forename: Sushma R
authors.initials: SR
authors.lastname: Gundala
authors.forename: Bharat
authors.initials: B
authors.lastname: Baruah
authors.forename: Mulpuri
authors.initials: M
authors.lastname: Nagaraju
authors.forename: Clayton
authors.initials: C
authors.lastname: Yates
authors.forename: Timothy
authors.initials: T
authors.lastname: Turner
authors.forename: Vijay
authors.initials: V
authors.lastname: Rangari
authors.forename: Donald
authors.initials: D
authors.lastname: Hamelberg
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Reid
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D002152:Calorimetry, Differential Scanning; D003505:Cyclodextrins / Q000737:chemistry*; D005685:Galactans / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D008351:Mannans / Q000737:chemistry*; D008863:Microspheres; D009665:Noscapine / Q000737:chemistry*; D053149:Plant Gums / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D003505:Cyclodextrins; D005685:Galactans; D008351:Mannans; D053149:Plant Gums; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D009665:Noscapine; C007894:guar gum
keywords: Red-Br-Nos; colon cancer; cytotoxicity; guar gum microspheres (GGMs); methyl-β-cyclodextrin (methyl-β-CD); β-cyclodextrin (β-CD)