Upconversion nanoparticles conjugated with Gd(3+) -DOTA and RGD for targeted dual-modality imaging of brain tumor xenografts.

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors in human. Small molecular magnetic resonance imaging (MRI) contrast agents are used for GBM diagnosis. However, conventional contrast agents have several limitations, such as low T1 relaxivity, short circulation half lives and absence of tumor targeting. Herein, we develop an upconversion nanoprobe labeled with Gd(3+) -DOTA and RGD (UCNP-Gd-RGD) for dual-modality imaging of glioblastoma. The preparation of UCNP-Gd-RGD starts with amine-functional upconversion nanoparticle core, followed by PEGylation, Gd(3+) DOTA conjugation and RGD labeling. The obtained UCNP-Gd-RGD has improved colloidal stability and reduced cytotoxicity compared with the UCNP core counterpart. Meanwhile, UCNP-Gd-RGD shows strong upconversion luminescence in deep-red region and three times enhancement of T1 relaxivity over Gd(3+) DOTA. Due to the recognition between UCNP-Gd-RGD and integrin αv β3 receptors, the nanoprobe specifically binds to U87MG cells, as evidenced by confocal microscopy and quantified by ICP-MS. Furthermore, UCNP-Gd-RGD demonstrates a preferential retention in subcutaneous U87MG tumor xenograft as shown in both in vivo upconversion fluorescence/MR imaging studies and ex vivo analysis. UCNP-Gd-RGD, conjugated with numerous RGD peptide and T1 contrast enhancing molecules, is promising for MR imaging of glioblastoma and delineating the tumor boundary before surgery. In addition, NIR-to-red upconversion characteristic of UCNP-Gd-RGD facilitates its potential intra-operative use for fluorescence-guided tumor resection.

• Authors: Jiefu Jin, Zhenhua Xu, Yue Zhang, Yan-Juan Gu, Michael Hon-Wah Lam, Wing-Tak Wong
• Journal: Advanced healthcare materials (Adv Healthc Mater) Vol. 2 Issue 11 Pg. 1501-12 (Nov 2013) ISSN: 2192-2659 [Electronic] Germany
• PMID: 23630101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Heterocyclic Compounds
• Oligopeptides
• Organometallic Compounds
• arginyl-glycyl-aspartic acid
• gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate

Topics

• Animals
• Brain Neoplasms (diagnosis)
• Cell Death (drug effects)
• Cell Line, Tumor
• Endocytosis (drug effects)
• Heterocyclic Compounds (chemistry)
• Humans
• Magnetic Phenomena
• Magnetic Resonance Imaging
• Mice, Inbred BALB C
• Mice, Nude
• Multimodal Imaging
• Nanoparticles (chemistry, ultrastructure)
• Oligopeptides
• Organometallic Compounds (chemistry)
• Spectrophotometry, Atomic
• Surface Properties
• Xenograft Model Antitumor Assays