A T1/T2 dual functional iron oxide MRI contrast agent with super stability and low hypersensitivity benefited by ultrahigh carboxyl group density.

Clinically acceptable safety and efficacy are the most important issues for the design and synthesis of iron oxide MRI contrast agents. In order to meet the practical requirements, a kind of low molecular weight PAA-coated Fe3O4 nanoparticle (CS015) with super colloidal stability and low hypersensitivity benefitting from an ultrahigh carboxyl group density was developed in this study. The composition and physicochemical properties of the particles were characterized by TEM, XRD, FTIR and TGA. The ultrahigh density of COOH on the particles (33 COOH per nm2) was verified while a core size of 5.1 nm and a dynamic diameter of 41 nm with a narrow distribution were also achieved. The particles still showed excellent dispersity and stability even after a spray-drying or freeze-drying process, exposure to high temperature sterilized conditions and long-term storage. The nanoparticles could quickly capture iron ions in bulk solution which was confirmed by ITC results, and the bioactive iron concentration of CS015 was greatly decreased (0.54 ± 0.05 mg L-1) compared to that of commercially available ferumoxytol, iron sucrose and VSOP. Free iron ion release was 1120 times lower than the toxic concentration of iron. An excellent biocompatibility of CS015 with no obvious cytotoxicity and low risk of hypersensitivity has been manifested by cytotoxicity experiments and a passive cutaneous anaphylaxis test. The T1 and T2-weighted MRI contrast effects both in vitro and in vivo have also been verified which made CS015 a potential dual MRI contrast agent. Furthermore, theoretically calculated conformation was speculated and all the advantages mentioned above were benefited from the three dimensional brush-like texture of CS015. Therefore, these merits make the CS015 nanoplatform highly suitable in diagnostic applications as a MRI contrast agent.

cRGD-Conjugated Fe3O4@PDA-DOX Multifunctional Nanocomposites for MRI and Antitumor Chemo-Photothermal Therapy.

BACKGROUND: Photothermal therapy (PTT) has great potential in the clinical treatment of tumors. However, most photothermal materials are difficult to apply due to their insufficient photothermal conversion efficiencies (PCEs), poor photostabilities and short circulation times. Furthermore, tumor recurrence is likely to occur using PTT only. In the present study, we prepared cyclo (Arg-Gly-Asp-d-Phe-Cys) [c(RGD)] conjugated doxorubicin (DOX)-loaded Fe3O4@polydopamine (PDA) nanoparticles to develop a multifunctional-targeted nanocomplex for integrated tumor diagnosis and treatment. MATERIALS AND METHODS: Cytotoxicity of Fe3O4@PDA-PEG-cRGD-DOX against HCT-116 cells was determined by cck-8 assay. Cellular uptake was measured by confocal laser scanning microscope (CLSM). Pharmacokinetic performance of DOX was evaluated to compare the differences between free DOX and DOX in nanocarrier. Performance in magnetic resonance imaging (MRI) and antitumor activity of complex nanoparticles were evaluated in tumor-bearing nude mice. RESULTS: Fe3O4@PDA-PEG-cRGD-DOX has a particle size of 200-300 nm and a zeta potential of 22.7 mV. Further studies in vitro and in vivo demonstrated their excellent capacity to target tumor cells and promote drug internalization, and significantly higher cytotoxicity with respect to that seen in a control group was shown for the nanoparticles. In addition, they have good thermal stability, photothermal conversion efficiencies (PCEs) and pH responsiveness, releasing more DOX in a mildly acidic environment, which is very conducive to their chemotherapeutic effectiveness in the tumor microenvironment. Fe3O4@PDA-PEG-cRGD-DOX NPs were used in a subcutaneous xenograft tumor model of nude mouse HCT-116 cells showed clear signal contrast in T2-weighted images and effective anti-tumor chemo-photothermal therapy under NIR irradiation. CONCLUSION: According to our results, Fe3O4@PDA-PEG-cRGD-DOX had a satisfactory antitumor effect on colon cancer in nude mice and could be further developed as a potential integrated platform for the diagnosis and treatment of cancer to improve its antitumor activity against colon cancer.

Strategy to prevent cardiac toxicity induced by polyacrylic acid decorated iron MRI contrast agent and investigation of its mechanism.

Polyelectrolyte modified iron oxide nanoparticles have great potential applications for clinical magnetic resonance imaging (MRI) and anemia treatments, however, possible associated heart toxicity is rarely reported. Here, polyacrylic acid (PAA)-coated Fe3O4 nanoparticles (PION) were synthesized and lethal reactions appeared when it was applied in vivo. The investigation of underlying mechanism showed that PION could break electrolyte balance and further resulted in serious heart failure, which was observed under color doppler ultrasound and dynamic vector blood flow technique. The results demonstrated that PION had a strong absorption tendency for divalent ions and the maximum tolerated dose (MTD) was lower than 100 mg/kg. From electrocardiography (ECG), PION presented an obvious impact on CaV1.2 ion channel, which leading to fatal arrhythmia. An appropriate solution for preventing this deadly effect was pre-chelation Ca2+ (n (Ca): n (COOH) = 3: 8) to PION (PION-Ca), which displayed much higher cardiac and electrophysiological safety when sealing the binding point of divalent cation ions with PAA. The injection in Beagle dogs further confirmed the safety of PION-Ca. This study explored the mechanism and offered a solution for cardiac toxicity induced by PAA-coated nanoparticles, which guides for enhancing the safety of such polyelectrolyte decorated nanoparticles and provides assurance for clinical applications.