NLG919/cyclodextrin complexation and anti-cancer therapeutic benefit as a potential immunotherapy in combination with paclitaxel.

Abstract

NLG919 is an effective small molecule inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO-1) in anti-tumour immunotherapy, but the poor aqueous solubility limits its application for effective intravenous dosing. In this study a cyclodextrin (CD) complexation strategy has been systematically evaluated to achieve a simple and feasible method to prepare an NLG919 injectable formulation. From a series of CDs, HP-β-CD proved to be the most conducive for NLG919 solubilization (approx 800-fold increase). Characterization studies using DSC, 1H NMR, XRPD and molecular simulation demonstrated that the NLG919/HP-β-CD loading mechanism involved an increasing pH-dependent binding affinity. Importantly cell-based studies in vitro and anti-tumour activity in vivo demonstrated that the pharmacological activity of NLG919 as an IDO-1 inhibitor was not influenced by HP-β-CD complexation. Furthermore, the combination of NLG919/HP-β-CD with paclitaxel (PTX) significantly improved anti-tumour chemotherapy compared to PTX alone. In summary, NLG919/HP-β-CD is shown to highly enhance the aqueous solubility of NLG919 with activity unaffected, greatly facilitating the intravenous use of this small molecule immunotherapeutic to improve the efficacy of PTX.

• Authors: Jian Xu, Xiaohong Ren, Tao Guo, Xian Sun, Xiaojin Chen, Laurence H Patterson, Haiyan Li, Jiwen Zhang
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 138 Pg. 105034 (Oct 01 2019) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 31382032 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• 1-cyclohexyl-2-(5H-imidazo(5,1-a)isoindol-5-yl)ethanol
• Antineoplastic Agents
• Cyclodextrins
• Imidazoles
• Immunologic Factors
• Isoindoles
• Small Molecule Libraries
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Calorimetry, Differential Scanning (methods)
• Cell Line, Tumor
• Cyclodextrins (therapeutic use)
• Female
• HeLa Cells
• Humans
• Imidazoles (therapeutic use)
• Immunologic Factors (therapeutic use)
• Immunotherapy (methods)
• Isoindoles (therapeutic use)
• Magnetic Resonance Spectroscopy (methods)
• Mice
• Mice, Inbred BALB C
• Neoplasms (drug therapy)
• Paclitaxel (therapeutic use)
• Small Molecule Libraries (therapeutic use)
• Solubility (drug effects)