Lactobionic/Folate Dual-Targeted Amphiphilic Maltodextrin-Based Micelles for Targeted Codelivery of Sulfasalazine and Resveratrol to Hepatocellular Carcinoma

• Published in: Bioconjugate chemistry 2018-09, Vol.29 (9), p.3026-3041
• Main Authors: Anwar, Doaa M, Khattab, Sherine N, Helmy, Maged W, Kamal, Mohamed K, Bekhit, Adnan A, Elkhodairy, Kadria A, Elzoghby, Ahmed O
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antibiotics; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor activity; Antitumor agents; Apoptosis; Asialoglycoprotein receptors; Biocompatibility; Body weight; Cancer therapies; Carbodiimide; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Conjugation; Coupling; Cytotoxicity; Disaccharides - chemistry; Drug delivery; Drug Delivery Systems; Folic acid; Folic Acid - chemistry; Hep G2 Cells; Hepatocellular carcinoma; Hepatocytes; Humans; Hydrophobicity; Internalization; Liver; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Maltodextrin; Mice; Micelles; Polymers; Polysaccharides - chemistry; Receptors; Resveratrol; Resveratrol - administration & dosage; Resveratrol - therapeutic use; Sulfasalazine; Sulfasalazine - administration & dosage; Sulfasalazine - therapeutic use; Toxicity; Tumors; Ursodeoxycholic acid; Vitamin B; Xenograft Model Antitumor Assays
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.8b00428

In this study, promising approaches of dual-targeted micelles and drug–polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.