title: MRI virtual biopsy and treatment of brain metastatic tumors with targeted nanobioconjugates: nanoclinic in the brain.
abstract: Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy, which can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections, or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise noninvasive MRI diagnostic method, we have engineered a new class of poly(β-l-malic acid) polymeric nanoimaging agents (NIAs). The NIAs carrying attached MRI tracer are able to pass through the blood-brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in a significant increase in animal survival and markedly reduced immunostaining for several cancer stem cell markers. Novel NIAs could be useful for brain diagnostic MRI in the clinic without currently performed brain biopsies. This technology shows promise for differential MRI diagnosis and treatment of brain metastases and other pathologies when biopsies are difficult to perform.
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.affiliation: #Arrogene Inc., Los Angeles, California, United States.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.forename: Pallavi R
authors.initials: PR
authors.lastname: Gangalum
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Jose
authors.initials: J
authors.lastname: Portilla-Arias
authors.forename: Shawn
authors.initials: S
authors.lastname: Wagner
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.forename: Arthur
authors.initials: A
authors.lastname: Rekechenetskiy
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chesnokova
authors.forename: Janet L
authors.initials: JL
authors.lastname: Markman
authors.affiliation: §Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Ljubimov
authors.forename: Debiao
authors.initials: D
authors.lastname: Li
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Prasad
authors.affiliation: #Arrogene Inc., Los Angeles, California, United States.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.affiliation: #Arrogene Inc., Los Angeles, California, United States.
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.affiliation: #Arrogene Inc., Los Angeles, California, United States.
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D000818:Animals; D001483:Base Sequence; D001706:Biopsy / Q000379:methods*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003937:Diagnosis, Differential; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D058726:Nanoconjugates / Q000737:chemistry; D050997:Nanomedicine / Q000379:methods*; D009362:Neoplasm Metastasis; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D066246:ErbB Receptors; D058726:Nanoconjugates; D016376:Oligonucleotides, Antisense; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: MRI; blood−brain barrier; brain metastasis; nanoconjugate; nanomedicine; tumor targeting; tumor treatment