title: Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependent intracellular drug release.
abstract: Studies were conducted to develop antibody- and fluorescence-labeled superparamagnetic iron oxide nanoparticle (SPIO) nanotheranostics for magnetic resonance imaging (MRI) and fluorescence imaging of cancer cells and pH-dependent intracellular drug release. SPIO nanoparticles (10 nm) were coated with amphiphilic polymers and PEGylated. The antibody HuCC49ΔCH2 and fluorescent dye 5-FAM were conjugated to the PEG of iron oxide nanoparticles (IONPs). Anticancer drugs doxorubicin (Dox), azido-doxorubicin (Adox), MI-219, and 17-DMAG containing primary amine, azide, secondary amine, and tertiary amine, respectively, were encapsulated into IONPs. The encapsulation efficiency and drug release at various pHs were determined using LC-MS/MS. The cancer targeting and imaging were monitored using MRI and fluorescent microscopy in a colon cancer cell line (LS174T). The pH-dependent drug release, intracellular distribution, and cytotoxicity were evaluated using microscopy and MTS assay. The PEGylation of SPIO and conjugation with antibody and 5-FAM increased SPIO size from 18 to 44 nm. Fluorescent imaging, magnetic resonance imaging (MRI) and Prussian blue staining demonstrated that HuCC49ΔCH2-SPIO increased cancer cell targeting. HuCC49ΔCH2-SPIO nanotheranostics decreased the T(2) values in MRI of LS174T cells from 117.3 ± 1.8 ms to 55.5 ± 2.6 ms. The loading capacities of Dox, Adox, MI-219, and 17-DMAG were 3.16 ± 0.77%, 6.04 ± 0.61%, 2.22 ± 0.42%, and 0.09 ± 0.07%, respectively. Dox, MI-219 and 17-DMAG showed pH-dependent release while Adox did not. Fluorescent imaging demonstrated the accumulation of HuCC49ΔCH2-SPIO nanotheranostics in endosomes/lysosomes. The encapsulated Dox was released in acidic lysosomes and diffused into cytosol and nuclei. In contrast, the encapsulated Adox only showed limited release in endosomes/lysosomes. HuCC49ΔCH2-SPIO nanotheranostics target-delivered more Dox to LS174T cells than nonspecific IgG-SPIO and resulted in a lower IC(50) (1.44 μM vs 0.44 μM). The developed HuCC49ΔCH2-SPIO nanotheranostics provides an integrated platform for cancer cell imaging, targeted anticancer drug delivery and pH-dependently drug release.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.forename: Yanke
authors.initials: Y
authors.lastname: Yu
authors.forename: Y Andrew
authors.initials: YA
authors.lastname: Wang
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Amanda
authors.initials: A
authors.lastname: Welton
authors.forename: Craig
authors.initials: C
authors.lastname: Galbán
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000906:Antibodies / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D005290:Ferric Compounds / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000737:chemistry*; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D013499:Surface Properties; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D005290:Ferric Compounds; D005456:Fluorescent Dyes; C000499:ferric oxide; D011092:Polyethylene Glycols