Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery

Mol Pharm. 2014 Dec 1;11(12):4339-49. doi: 10.1021/mp500408n. Epub 2014 Nov 18.


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.

Keywords: Red-Br-Nos; colon cancer; cytotoxicity; guar gum microspheres (GGMs); methyl-β-cyclodextrin (methyl-β-CD); β-cyclodextrin (β-CD).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calorimetry, Differential Scanning
  • Cyclodextrins / chemistry*
  • Galactans / chemistry*
  • HT29 Cells
  • Humans
  • Mannans / chemistry*
  • Microspheres*
  • Noscapine / chemistry*
  • Plant Gums / chemistry*
  • Spectroscopy, Fourier Transform Infrared
  • beta-Cyclodextrins / chemistry


  • Cyclodextrins
  • Galactans
  • Mannans
  • Plant Gums
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin
  • Noscapine
  • guar gum