Anti-transferrin receptor-modified amphotericin B-loaded PLA–PEG nanoparticles cure Candidal meningitis and reduce drug toxicity

Abstract

Xiaolong Tang,1,2,* Yong Liang,3,* Yongqiang Zhu,1,4,* Chunmei Xie,5 Aixia Yao,1 Li Chen,1 Qinglin Jiang,1 Tingting Liu,1 Xiaoyu Wang,1 Yunyun Qian,1 Jia Wei,1 Wenxuan Ni,1 Jingjing Dai,1 Zhenyou Jiang,6,7,* Wei Hou2,* 1Clinical Laboratory, Huainan First People’s Hospital and First Affiliated Hospital of Medical College, Anhui University of Science & Technology, Huainan, 2State Key Laboratory of Virology/Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, 3Clinical Laboratory, Huai’an Hospital Affiliated of Xuzhou Medical College, Huaian, 4Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 5School of Biotechnology, Southern Medical University, 6Department of Microbiology and Immunology, School of Medicine, 7Guangdong Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Fatal fungal infections in central nervous system (CNS) can occur through hematogenous spread or direct extension. At present, hydrophobic amphotericin B (AMB) is the most effective antifungal drug in clinical trials. However, AMB is hydrophobic and therefore penetrates poorly into the CNS, and therapeutic levels of AMB are hard to achieve. The transferrin receptor (TfR/CD71) located at the blood–brain barrier mediates transferrin transcytosis. In order to enhance the receptor-mediated delivery of AMB into CNS with therapeutic level, an anti-TfR antibody (OX26)-modified AMB-loaded PLA (poly[lactic acid])–PEG (polyethylene glycol)-based micellar drug delivery system was constructed. The prepared OX26-modified AMB-loaded nanoparticles (OX26-AMB-NPs) showed significant reduction of CNS fungal burden and an increase of mouse survival time. In conclusion, OX26-AMB-NPs represent a promising novel drug delivery system for intracerebral fungal infection. Keywords: drug delivery, nanocarrier, amphotericin B, blood–brain barrier, transferrin receptor