Family of bioactive heparins-coated iron oxide nanoparticles with T1-positive magnetic resonance contrast for various biomedical applications

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) are well known for their anticoagulant properties with a large clinical use. There is also currently a growing interest in using heparins in targeted cancer... [ view full abstract ]

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) are well known for their anticoagulant properties with a large clinical use. There is also currently a growing interest in using heparins in targeted cancer therapy. In particular, several types have been described to inhibit heparanase, a key enzyme overexpressed in the tumor microenvironment for angiogenesis progression and metastasis spreading. Here, we propose iron oxide nanoparticles coated with various heparins (HEP-IONP) of distinct anticoagulant and anti-heparanase activity ratios suitable for T1- weighted MRI, a recent contrast obtained with IONP class considered as very promising for sustainable clinical applications. A one-step microwave-based method was adapted to produce small size HEP-IONP stable in physiological media, and importantly, showing relaxivity performances for positive contrast in T1-weighted MRI. As proof of concept, high-resolution magnetic resonance angiography at large magnetic field were succeeded in mice up to 3 hours after intravenous administration of the probes. This unusual IONP-based positive contrast and the long vascular circulating times combined with the different bioactivities of the heparins enable innovative theranostic applications. We showed using advanced in vitro tests, how HEP-IONP anticoagulant and anti-heparanase activities were maintained depending on the type of heparin used for the coating. This confirmed that because they are polymeric substrates, specific heparin species can entered in the nanoparticle formulation at the same time as stabilizing surfactant and as particular bioactive group. Overall, the study allowed presenting an IONP coated with a commercial LMWH (Lovenox ®) as a theranostic translational probe for diagnostic magnetic resonance angiography and treatment of thrombosis, and an IONP coated with a specific depolymerized heparin that could be a potential anti-tumor candidate to be used in targeted therapy and diagnostic modalities.

[1] Oduah EI, Linhardt RJ, Sharfstein ST. Pharm Basel Switz. 2016;9(3).

[2] Niers TMH, Klerk CPW, DiNisio M, Van Noorden CJF, Büller HR, Reitsma PH, et al. 2007 Mar;61(3):195–207.

[3] Rivara S, Milazzo FM, Giannini G. Future Med Chem. 2016 Apr;8(6):647–80.

[4] Masola V, Secchi MF, Gambaro G, Onisto M. Curr Cancer Drug Targets. 2014;14(3):286–93.