The Effects of a Novel Curcumin Derivative Loaded Long-Circulating Solid Lipid Nanoparticle on the MHCC-97H Liver Cancer Cells and Pharmacokinetic Behavior

Abstract

Yumeng Wei,1– 3,* Ke Li,1– 3,* Wenmei Zhao,1– 3,* Yingmeng He,2,4 Hongping Shen,2,5 Jiyuan Yuan,2,5 Chao Pi,1– 3 Xiaomei Zhang,6 Mingtang Zeng,1– 3 Shaozhi Fu,7 Xinjie Song,8,9 Robert J Lee,10 Ling Zhao2,3 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 4Department of Pharmacy, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 5Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 6Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, Institute of Medicinal Chemistry of Chinese Medicine, Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, People’s Republic of China; 7Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 8School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang, 310023, People’s Republic of China; 9Department of Food Science and Technology, Yeungnam University, Gyeongsan-si, Gyeongsangbuk-do, 38541, Republic of Korea; 10Division of Pharmaceutics and Pharmacology, College of Pharmacy, the Ohio State University, Columbus, OH, 43210, USA*These authors contributed equally to this workCorrespondence: Robert J Lee, The Ohio State University, 500 W 12th Ave, Columbus, OH, 43210, USA, Tel [phone], Fax [phone], Email [email protected] Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: The objective of this study was to develop long-circulating solid lipid nanoparticles (LSLN) containing a novel curcumin (CU) derivative (CU1), to improve CU1ʹs pharmacokinetic behavior and its anti-cancer effects in MHCC-97H liver cancer cells.Methods: LSLN loaded with CU1 (CU1-LSLN) was optimized and characterized. The cell biological properties and the anti-cancer mechanism of CU1-LSLN on MHCC-97H cells were evaluated by MTT, flow cytometry, Transwell, and Western blot. CU1-LSLN was further evaluated for pharmacokinetic behavior, biodistribution, and liver toxicity in SD rats.Results: The optimized CU1-LSLN formulation showed the ideal particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and drug loading (DL%) of 122.10 ± 6.63 nm, 0.19 ± 0.02, − 36.30 ± 1.25 mV, 94.98 ± 0.90% and 4.53 ± 0.69%, respectively. X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR) indicated that CU1 was well encapsulated by LSLN and existed in amorphous form. Storage stability of CU1-LSLN was up to 180 days with a sustained-release of drug over 96 h. The uptake efficiency of CU1-LSLN to MHCC-97H cells was 3.24 and 2.98 times higher than that of CU and CU1 after treatment for 3 h, which helped to enhance the inhibitive effect of CU1-LSLN on the proliferation, migration, and invasion potential of MHCC-97H cells and increased its ability to promote apoptosis. Meanwhile, the expression levels of NF-κB, COX-2, MMP-2, MMP-9, and uPA decreased significantly. In vivo, CU1-LSLN prolonged the retention time of the drug, the area under the curve (AUC) increased significantly (CU: 69.9-fold, CU1: 85.9-fold), and no significant liver toxicity was observed.Conclusion: CU1-LSLN is a novel preparation with great potential for treating liver cancer.Keywords: curcumin derivative, nanoparticle, MHCC-97H, pharmacokinetics

Keywords

• curcumin derivative
• nanoparticle
• mhcc-97h
• pharmacokinetics