Molecular Cycloencapsulation Augments Solubility and Improves Therapeutic Index of Brominated Noscapine in Prostate Cancer Cells

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• 作者：Jitender Madan ; Bharat Baruah ; Mulpuri Nagaraju ; Mohamed O. Abdalla ; Clayton Yates ; Timothy Turner ; Vijay Rangari ; Donald Hamelberg ; Ritu Aneja
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：May 7, 2012
• 年：2012
• 卷：9
• 期：5
• 页码：1470-1480
• 全文大小：520K
• 年卷期：v.9,no.5(May 7, 2012)
• ISSN：1543-8392

文摘

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 尾-CD and methyl-尾-CD, with a stability constant (K_c) of 2.42 脳 10^鈥? M and 4.85 脳 10^鈥? M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O鈥揅H₂ or OCH₃鈥揅₆H₄鈥揙CH₃ moiety of EM011 in the 尾-CD or methyl-尾-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 尾-CD and methyl-尾-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H_a proton of the OCH₃鈥揅₆H₄鈥揙CH₃ moiety was in close proximity with H3 proton of the 尾-CD or methyl-尾-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 尾-CD and methyl-尾-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC₅₀ to 28.5 渭M (9-Br-Nos-尾-CD) and 12.5 渭M (9-Br-Nos-methyl-尾-CD) in PC-3 cells compared to free EM011 (200 渭M). 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.

Keywords:

EM011; 尾-CD; methyl-尾-CD; inclusion complexes; dissolution; cytotoxicity; prostate cancer