title: Long-circulating heparin-functionalized magnetic nanoparticles for potential application as a protein drug delivery platform.
abstract: Starch-coated, PEGylated, and heparin-functionalized iron oxide magnetic nanoparticles (DNPH) were successfully synthesized and characterized in detail. The PEGylation (20 kDa) process resulted in an average coating of 430 PEG molecules per nanoparticle. After that, heparin conjugation was carried out to attain the final DNPH platform with 35.4 μg of heparin/mg of Fe. Commercially acquired heparin-coated magnetic nanoparticles were also PEGylated (HP) and characterized for comparison. Protamine was selected as a model protein to demonstrate the strong binding affinity and high loading content of DNPH for therapeutically relevant cationic proteins. DNPH showed a maximum loading of 22.9 μg of protamine/mg of Fe. In the pharmacokinetic study, DNPH displayed a long-circulating half-life of 9.37 h, 37.5-fold longer than that (0.15 h) of HP. This improved plasma stability enabled extended exposure of DNPH to the tumor lesions, as was visually confirmed in a flank 9L-glioma mouse model using magnetic resonance imaging (MRI). Quantitative analysis of the Fe content in excised tumor lesions further demonstrated the superior tumor targeting ability of DNPH, with up to 31.36 μg of Fe/g of tissue (13.07% injected dose (I.D.)/g of tissue) and 7.5-fold improvement over that (4.27 μg of Fe/g of tissue; 1.78% I.D./g of tissue) of HP. Overall, this study shed light on the potential of DNPH to be used as a protein drug delivery platform.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University , Tianjin 300070, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Meong Cheol
authors.initials: MC
authors.lastname: Shin
authors.forename: Allan E
authors.initials: AE
authors.lastname: David
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Kyuri
authors.initials: K
authors.lastname: Lee
authors.forename: Huining
authors.initials: H
authors.lastname: He
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D005290:Ferric Compounds / Q000737:chemistry; D005910:Glioma / Q000175:diagnosis / Q000378:metabolism; D006493:Heparin / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D011479:Protamines / Q000737:chemistry
chemical_list: D005290:Ferric Compounds; D011479:Protamines; C000499:ferric oxide; D006493:Heparin
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