Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma

Bin Wang; Lin Sun; Mingyun Wen; Youchun Tan; Waleed H Almalki; Hanadi Katouah; Imran Kazmi; Obaid Afzal; Abdulmalik Saleh Alfawaz Altamimi; Fahad A Al-Abbasi; Majed Alrobaian; Khalid S Alharbi; Sattam K Alenezi; Adel F Alghaith; Sarwar Beg; Mahfoozur Rahman

doi:10.1016/j.jsps.2021.06.006

Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma

Saudi Pharm J. 2021 Aug;29(8):843-856. doi: 10.1016/j.jsps.2021.06.006. Epub 2021 Jun 30.

Authors

Bin Wang¹, Lin Sun², Mingyun Wen², Youchun Tan³, Waleed H Almalki⁴, Hanadi Katouah⁵, Imran Kazmi⁶, Obaid Afzal⁷, Abdulmalik Saleh Alfawaz Altamimi⁷, Fahad A Al-Abbasi⁶, Majed Alrobaian⁸, Khalid S Alharbi⁹, Sattam K Alenezi¹⁰, Adel F Alghaith¹¹, Sarwar Beg¹², Mahfoozur Rahman¹³

Affiliations

¹ Department of Oncology Minimally Invasive, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences), Jinan, Shandong Province 250031, China.
² Department of Radiology, Binzhou People's Hospital, Binzhou, Shandong Province 256610, China.
³ Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicne, Shandong University, No.11 Wuying Shanzhong Road, Jinan City, Shandong Province 250031, China.
⁴ Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁵ Chemistry Department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
⁶ Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, AlKharj, Saudi Arabia.
⁸ Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia.
⁹ Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah, Saudi Arabia.
¹⁰ Department of Pharmacology & Toxicology, Unaizah College of Pharmacy, Qassim University, Qassim, Saudi Arabia.
¹¹ Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
¹² Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
¹³ Department of Pharmaceutical Sciences, Shalom Institute of Health & Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad, India.

Abstract

The current study focuses on the development and evaluation of nano lipidic carriers (NLCs) for codelivery of sorafenib (SRF) and ganoderic acid (GA) therapy in order to treat hepatocellular carcinoma (HCC). The dual drug-loaded NLCs were prepared by hot microemulsion technique, where SRF and GA as the drugs, Precirol ATO5, Capmul PG8 as the lipids, while Solutol HS15 and ethanol was used as surfactant and cosolvents. The optimized drug-loaded NLCs were extensively characterized through in vitro and in vivo studies. The optimized formulation had particle size 29.28 nm, entrapment efficiency 93.1%, and loading capacity 14.21%. In vitro drug release studies revealed>64% of the drug was released in the first 6 h. The enzymatic stability analysis revealed stable nature of NLCs in various gastric pH, while accelerated stability analysis at 25^◦C/60% RH indicated the insignificant effect of studied condition on particle size, entrapment efficiency, and loading capacity of NLCs. The cytotoxicity performed on HepG2 cells indicated higher cytotoxicity of SRF and GA-loaded NLCs as compared to the free drugs (p < 0.05). Furthermore, the optimized formulation suppressed the development of hepatic nodules in the Wistar rats and significantly reduced the levels of hepatic enzymes and nonhepatic elements against DEN intoxication. The SRF and GA-loaded NLCs also showed a significant effect in suppressing the tumor growth and inflammatory cytokines in the experimental study. Further, histopathology study of rats treated SRF and GA-loaded NLCs and DEN showed absence of necrosis, apoptosis, and disorganized hepatic parenchyma, etc. over other treated groups of rats. Overall, the dual drug-loaded NLCs outperformed over the plain drugs in terms of chemoprotection, implying superior therapeutic action and most significantly eliminating the hepatic toxicity induced by DEN in Wistar rat model.

Keywords: Antioxidants; Hepatocellular carcinoma; Inflammatory markers; Nanolipdic carrier; Nonhepatic parameters; Sorafenib.