Research Article For reprint orders, please contact: reprints@futuremedicine.com Decorating protein nanospheres with lactoferrin enhances oral COX-2 inhibitor/herbal therapy of hepatocellular carcinoma Mona A Abdelmoneem 1,2 , Mazen Mahmoud 3 , Amira Zaky 3 , Maged W Helmy 1,4 , Marwa Sallam 2 , Jia-You Fang 5,6,7 , Kadria A Elkhodairy 1,2 & Ahmed O Elzoghby* ,1,2,8,9 1 Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt 2 Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt 3 Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria 21511, Egypt 4 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Damanhur University, Damanhur 22511, Egypt 5 Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan 6 Research Center for Industry of Human Ecology & Research Center for Chinese Herbal Medicine, Chang Gung University of Science & Technology, Kweishan, Taoyuan 333, Taiwan 7 Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan 8 Division of Engineering in Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 9 Harvard-MIT Division of Health Sciences and Technologies, Cambridge, MA 02139, USA *Author for correspondence: Tel.: +1 781 366 8703; aelzoghby@bwh.harvard.edu Aim: Lactoferrin (LF)-targeted gliadin nanoparticles (GL-NPs) were developed for targeted oral therapy of hepatocellular carcinoma. Materials & methods: Celecoxib and diosmin were incorporated in the hy- drophobic matrix of GL-NPs whose surface was decorated with LF by electrostatic interaction for binding to asialoglycoprotein receptors overexpressed by liver cancer cells. Results: Targeted GL-NPs showed en- hanced cytotoxic activity and increased cellular uptake in liver tumor cells compared with nontargeted NPs. Moreover, they demonstrated superior in vivo antitumor effects including reduction in the expres- sion levels of tumor biomarkers and induction of caspase-mediated apoptosis. Ex vivo imaging of isolated organs exhibited extensive accumulation of NPs in livers more than other organs. Conclusion: LF-targeted GL-NPs could be considered as an effcient nanoplatform for targeted oral drug delivery for liver cancer therapy. First draft submitted: 19 April 2018; Accepted for publication: 10 July 2018; Published online: 22 October 2018 Keywords: COX-2 inhibitors • diosmin • gliadin nanoparticles • hepatocellular carcinoma • lactoferrin-targeting • oral delivery Hepatocellular carcinoma (HCC) is one of the most malignant types of liver cancers [1]. Surgical resection is believed as the optimal treatment for HCC, but this is not always feasible as many patients are diagnosed in the late stage or underlying liver dysfunction. Moreover, traditional cytotoxic chemotherapy is not successful in improving the survival rate of liver cancer patients and is associated with significant toxicities due to the lack of tumor selectivity [2]. Nanoparticle (NP)-based drug carriers are employed to improve the therapeutic outcome of chemotherapeutic drugs through targeting the desired cells, which offers the potential for a successful HCC therapy [3–5]. Celecoxib (CXB), a nonsteroidal anti-inflammatory drug, selectively inhibits the COX-2 enzyme overexpressed in various cancer tissues. It was reported that COX-2 enzyme has an important contribution to hepatocarcinogenesis; thus, selective COX-2 inhibitors, for example, CXB showed antiproliferative and proapoptotic actions in HCC cells [6]. Moreover, selective COX-2 inhibitors (CXB) have been shown to act additionally through COX-2- independent mechanisms, indicating that CXB can be considered as efficient therapy of HCC by both COX-2- dependent and independent mechanisms [7]. On the other hand, diosmin (DSN) is a potent herbal drug with Nanomedicine (Lond.) (Epub ahead of print) ISSN 1743-5889 10.2217/nnm-2018-0134 C  2018 Future Medicine Ltd