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
Affiliations
Muhammad Inam
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
Yi Yang
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
Jialin Hu
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
Jiena Zheng
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
Wenxia Deng
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
You Zhou
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
Jialong Qi
Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming 650032, China
Chuanshan Xu
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
Guihong Chai
School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China
Yuanye Dang
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
Wenjie Chen
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
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.
