Self-assembled, biocompatible and biodegradable TEMPO-conjugated nanoparticles enable folate-targeted tumor magnetic resonance imaging. (March 2020)

• Record Type: Journal Article
• Authors: Akakuru, Ozioma Udochukwu; Iqbal, M. Zubair; Liu, Chuang; Xing, Jie; Wei, Zhenni; Jiang, Zhenqi; Fang, Qianlan; Yuan, Bo; Nosike, Elvis Ikechukwu; Xia, Jianbi; Jin, Yinhua; Zheng, Jianjun; Wu, Aiguo
• Is Part Of: Applied materials today. Volume 18(2020)
• Publication Date: 2020-03
• Subjects: Chitosan -- Folate receptor -- MRI -- Organic nitroxide radical -- Tumor targeting; Materials science -- Periodicals; Materials -- Research -- Periodicals; 620.1105
• DOI: 10.1016/j.apmt.2019.100524
• Languages: English
• ISSNs: 2352-9407

Abstract

Graphical abstract: Highlights: A new application for chitosan-TEMPO (CS-TEMPO) is uncovered for the first time. Carefully selecting starting materials obviated the conventional use of metal-based catalysts for similar synthesis Compartmentalization of TEMPO in CS greatly reduced its ease of in vivo reduction. Folic acid-decorated CS-TEMPO (CS-TEMPO-FA) can be taken up by various tumor cells. The totally metal-free CS-TEMPO-FA provides safe and commensurate tumor-targeted MRI. Abstract: Magnetic resonance imaging (MRI) signal intensities in tissues are usually enhanced by the injection of metal-based contrast agents (CAs) in patients. Some of these metal compounds have been linked to incurable nephrogenic systemic fibrosis and other neurological disorders, leading to their discontinuation. Herein, we report the design, synthesis, and characterization of a self-assembled metal-free CA which is based on an organic nitroxide radical (4-carboxy-TEMPO) compartmentalized in the biocompatible, biodegradable natural polymer, chitosan (CS), alongside folate targeting for in vivo tumor MRI. This extension conceivably heralds a new application for CS-TEMPO, which hitherto was used in macro-sizes as initiators for grafting CS to various polymers. Significantly, the folic acid (FA)-modified metal-free CA (CS-TEMPO-FA; average size ∼113 nm) is substantially benign, with no evidence of acute toxicity; it exhibits desirable pharmacokinetic profile, enhanced stability in highly reducing environments, high nitroxide loading (molecular relaxivity ∼18.56 mM −1 s −1 ), and effective tumor targeting. This latter characteristic ameliorates the non-specific uptake of CAs by normal cells. CS-TEMPO-FA nanoparticles demonstrate commensurate contrast enhancement of the tumor region up to 1 h post-injection when injected into 4T1 tumor-bearing mice, a contrast enhancement capability hitherto unattained by TEMPO-based CAs. This work points to CS-TEMPO-FA as a potential alternative to metal-based CAs as well as an active folate-targeted metal-free CA for long-term longitudinal tumor MRI which ameliorates the otherwise short in vivo lifetimes of typical organic radicals-based CAs.