title: A multifunctional polymeric nanotheranostic system delivers doxorubicin and imaging agents across the blood-brain barrier targeting brain metastases of breast cancer.
abstract: Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.forename: Alireza
authors.initials: A
authors.lastname: Shalviri
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Henderson
authors.forename: Chunsheng
authors.initials: C
authors.lastname: He
authors.forename: Warren D
authors.initials: WD
authors.lastname: Foltz
authors.forename: Preethy
authors.initials: P
authors.lastname: Prasad
authors.forename: Peter M
authors.initials: PM
authors.lastname: Brodersen
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Chen
authors.forename: Ralph
authors.initials: R
authors.lastname: DaCosta
authors.forename: Andrew Michael
authors.initials: AM
authors.lastname: Rauth
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging; D051379:Mice
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: blood−brain barrier; brain metastases of breast cancer; chemotherapy; doxorubicin; multifunctional polymer; polysorbate 80; theranostic nanoparticle