Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Muhammad Inam; Yi Yang; Jialin Hu; Jiena Zheng; Wenxia Deng; You Zhou; Jialong Qi; Chuanshan Xu; Guihong Chai; Yuanye Dang; Wenjie Chen

doi:10.3390/pharmaceutics15122713

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

Pharmaceutics. 2023 Nov 30;15(12):2713. doi: 10.3390/pharmaceutics15122713.

Authors

Muhammad Inam¹, Yi Yang¹, Jialin Hu¹, Jiena Zheng¹, Wenxia Deng¹, You Zhou¹, Jialong Qi², Chuanshan Xu¹, Guihong Chai³, Yuanye Dang¹, Wenjie Chen^{1

4}

Affiliations

¹ Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Science, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
² Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People's Hospital of Yunnan Province, Kunming 650032, China.
³ School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.
⁴ Sydney Vital Translational Cancer Research Centre, Westbourne St., Sydney, NSW 2065, Australia.

Abstract

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose.

Keywords: DNA damage and repair; co-formers; cocrystal; gefitinib; oral administration.

Grants and funding

This work was supported by the High-level University Construction Fund of Guangdong Province under grants (Nos 02-412-2302-2122XM, 02-410-2206298), the grants form Guangzhou Medical University (02-410-2302374XM and 02-445-2301221XM) for Dr. Dang, Guangdong Basic and Applied Basic Research Foundation (No. 2023A1515011064), the Postdoctoral Start-up fund (No. Q0301-082) for Dr. Inam, the fund (No. 202201010378) from Guangzhou Science and Technology Bureau, and the Open Project of State Key Laboratory of Respiratory Disease (No. SKLRD-OP-202409 for Dr. Chen, No. SKLRD-OP-202302 for Dr. Chai).