title: Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.
abstract: In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 μg/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted selectively to FR-positive tumors and simultaneously providing targeted US imaging capabilities.
authors.affiliation: Department of Radiology, Taipei City Hospital, Taipei, Taiwan; Department of Radiology, School of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wei-Tsung
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shih-Tsung
authors.initials: ST
authors.lastname: Kang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Lin
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of Radiology, Taipei City Hospital, Taipei, Taiwan; Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ran-Chou
authors.initials: RC
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: ckyeh@mx.nthu.edu.tw.
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Yeh
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D049329:Nanostructures; D009369:Neoplasms / Q000188:drug therapy*; D000068936:Theranostic Nanomedicine; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005492:Folic Acid; D002166:Camptothecin
keywords: Acoustic nanodroplet vaporization; Camptothecin; EPR effect; Folate receptor targeting; Targeted tumor theranostics