Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery
Xiaolin Xu,
Shasha Gao,
Qindan Zuo,
Jiahao Gong,
Xinhao Song,
Yongshi Liu,
Jing Xiao,
Xiaofeng Zhai,
Haifeng Sun,
Mingzhi Zhang,
Xiuge Gao,
Dawei Guo
Affiliations
Xiaolin Xu
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Shasha Gao
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Qindan Zuo
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Jiahao Gong
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Xinhao Song
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Yongshi Liu
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Jing Xiao
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Xiaofeng Zhai
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Haifeng Sun
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Mingzhi Zhang
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Xiuge Gao
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Dawei Guo
Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1 Weigang, Nanjing 210095, China
Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.
