Oral Delivery of Anti-Parasitic Agent-Loaded PLGA Nanoparticles: Enhanced Liver Targeting and Improved Therapeutic Effect on Hepatic Alveolar Echinococcosis

Jun Li,1,&ast; Yangyang Yang,2,&ast; Xiumin Han,3,&ast; Jing Li,2 Mengxiao Tian,1 Wenjing Qi,1 Huniu An,3 Chuanchuan Wu,1 Yao Zhang,1 Shuai Han,4 Liping Duan,4 Weisi Wang,4 Wenbao Zhang1 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 4NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenbao Zhang; Weisi Wang, Tel +86 991 4366319 ; +86 21 64377008, Email wenbaozhang2013@163.com; wangws@nipd.chinacdc.cnBackground: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment.Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE.Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals.Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.Graphical Abstract: Keywords: alveolar echinococcosis, Echinococcus multilocularis, PLGA, nanoparticles, liver targeting, oral administration