title: Two-order targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain barrier.
abstract: Surgical resection is a mainstay of brain tumor treatments. However, the completed excision of malignant brain tumor is challenged by its infiltrative nature. Contrast enhanced magnetic resonance imaging is widely used for defining brain tumor in clinic. However its ability in tumor visualization is hindered by the transient circulation lifetime, nontargeting specificity, and poor blood brain barrier (BBB) permeability of the commercially available MR contrast agents. In this work, we developed a two-order targeted nanoprobe in which MR/optical imaging reporters, tumor vasculature targeted cyclic [RGDyK] peptides, and BBB-permeable Angiopep-2 peptides are labeled on the PAMAM-G5 dendrimer. This nanoprobe is supposed to first target the α(V)β(3) integrin on tumor vasculatures. Increased local concentration of nanoprobe facilitates the association between BBB-permeable peptides and the low-density lipoprotein receptor-related protein (LRP) receptors on the vascular endothelial cells, which further accelerates BBB transverse of the nanoprobe via LRP receptor-mediated endocytosis. The nanoprobes that have penetrated the BBB secondly target the brain tumor because both α(V)β(3) integrin and LRP receptor are highly expressed on the tumor cells. In vivo imaging studies demonstrated that this nanoprobe not only efficiently crossed intact BBB in normal mice, but also precisely delineated the boundary of the orthotropic U87MG human glioblastoma xenograft with high target to background signal ratio. Overall, this two-order targeted nanoprobe holds the promise to noninvasively visualize brain tumors with uncompromised BBB and provides the possibility for real-time optical-image-guided brain tumor resection during surgery.
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated with Fudan University, 180 Fenglin Road, Shanghai 200032, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Yan
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Jiyao
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Weng
authors.forename: Hao
authors.initials: H
authors.lastname: Lei
authors.forename: Xuxia
authors.initials: X
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
authors.forename: Xunbin
authors.initials: X
authors.lastname: Wei
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods*; D057054:Molecular Imaging / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry