Molecular cycloencapsulation augments solubility and improves therapeutic index of brominated noscapine in prostate cancer cells

Mol Pharm. 2012 May 7;9(5):1470-80. doi: 10.1021/mp300063v. Epub 2012 Apr 27.

Abstract

We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with β-CD and methyl-β-CD, with a stability constant (K(c)) of 2.42 × 10(-3) M and 4.85 × 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the β-CD or methyl-β-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with β-CD and methyl-β-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3)-C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the β-CD or methyl-β-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with β-CD and methyl-β-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 μM (9-Br-Nos-β-CD) and 12.5 μM (9-Br-Nos-methyl-β-CD) in PC-3 cells compared to free EM011 (~200 μM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.

Publication types

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

MeSH terms

  • Calorimetry, Differential Scanning
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclodextrins / chemistry*
  • Dioxoles / chemistry
  • Dioxoles / therapeutic use
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / therapeutic use
  • Magnetic Resonance Spectroscopy
  • Male
  • Noscapine / chemistry*
  • Noscapine / pharmacology*
  • Prostatic Neoplasms / metabolism*
  • Solubility
  • Spectroscopy, Fourier Transform Infrared
  • X-Ray Diffraction

Substances

  • Cyclodextrins
  • Dioxoles
  • EM011 compound
  • Isoquinolines
  • Noscapine