Izvorni znanstveni članak

https://doi.org/10.5599/admet.4.4.341

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

Srinivas Maddi orcid.org/0000-0002-7280-4900 ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Ravi Akkireddy ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Srinivas Lenkalapelly ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Pratima Srivastava ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Joshodeep Boruwa ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Chandra Deb ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Arnab Roy Chowdhury ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Duraiswamy A. Jeyaraj ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India
Ramana Reddy ; Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029
Premkumar Reddy ; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029
Manoj Maniar ; Onconova Therapeutics, Newtown, PA 18940
Sachin Bansal ; 5ASB life sciences PVT LTD., Nacharam, Hyderabad 500076, India
Jang B. Gupta ; GVK Biosciences PVT LTD., Nacharam, Hyderabad 500076, India

Sažetak

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression.

Ključne riječi

GBO-006; PLK2 inhibitor; Pharmacokinetics; Efficacy; Triple negative breast cancer

Hrčak ID:

171424

URI

https://hrcak.srce.hr/171424

Datum izdavanja:

26.12.2016.

Posjeta: 4.547 *