Chain Length Effect of the Multidentate Block Copolymer Strategy to Stabilize Ultrasmall Fe 3 O 4 Nanoparticles

et al. 2018

ACS Appl. Nano Mater.

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Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have been used as vascular contrast agents in magnetic resonance imaging (MRI), mainly for their capacity to generate negative contrast. To use USPIOs as positive contrast agents, it is necessary to achieve increased colloidal stability and signal-enhancement performance. Their molecular coatings must be carefully chosen, so that the vascular blood-pool contrast agents lead to long blood turnover times. However, to avoid long-term toxicological effects, they must also be cleared rapidly through the urinary or gastrointestinal pathways. In this context, highly stable USPIOs showing “positive” contrast in MRI and optimal clearance rates call for the development of robust biocompatible molecular coatings. In the present study, USPIOs were stabilized with a multidentate block copolymer (MDBC), using a one-pot polyol synthesis method in the presence of a MDBC. Two types of MDBCs having pendant COOH groups in the anchoring block were developed: a polymer with linear-poly(ethylene glycol) (PEG) blocks and a polymer containing brushed-PEG blocks. The synthesized superparamagnetic Fe3O4 crystals were uniform (5–8 nm in diameter), showed ultrasmall hydrodynamic diameters in dynamic light scattering, and were stable in physiological liquids. MDBC-coated USPIOs were analyzed in relaxometry, and the formulations showing the strongest potential for T 1-weighted vascular imaging (r 2/r 1: ∼4) were selected for in vivo MRI. Intravascular injections performed in the mouse model indicated long blood retention times and high signal enhancement in MRI for nanoparticles coated with linear-PEG block coatings. These results also indicate that MDBC/USPIOs could be used in vascular MRI applications, where the nanoparticles must transit the blood for several hours, followed by an efficient clearance in the next days following injection. The use of MDBCs as nanoparticle coatings could open new possibilities in the design of USPIOs for targeted molecular MRI.

Section: Introductionmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast in T₁-Weighted Magnetic Resonance Imaging

Xiao

Legros

et al. 2018

ACS Appl. Nano Mater.

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“…From the slopes, the relaxivity parameters for Cat‐MDBC/ESNPs were determined to be r 1 =3.0 mM −1 s −1 and r 2 =4.6 mM −1 s −1 , leading to the r 2 / r 1 ratio as low as 1.5. For the comparison with other SNP systems measured at similar magnetic field=1.41 T, this value appears to be lower than those ( r 2 / r 1 = 2.0‐5.5) for most PEG‐coated SNPs with core diameter=1.7‐5.4 nm, including clinically‐used Supravist with core diameter=3‐5 nm ( r 2 / r 1 = 3.6), as well as USNPs stabilized with MDBS having pendant carboxylic acid and catechol groups . Such a lower r 2 /r 1 ratio of Cat‐MDBC/ESNP colloids could stem from low r 2 relaxivity, which can be attributed to two factors: small core size (≈2 nm in diameter) and thick coating layer with water‐soluble dense POEOMA brush polymers .…”

Section: Resultsmentioning

confidence: 78%

Extremely Small Iron Oxide Nanoparticles Stabilized with Catechol‐Functionalized Multidentate Block Copolymer for Enhanced MRI

Xiao

et al. 2016

ChemistrySelect

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An effective mussel-inspired multidentate block copolymer strategy having pendant anchoring catechol groups (Cat-MDBC) to stabilize extremely small iron oxide nanoparticles (ESNPs) in water is reported. The resultant aqueous Cat-MDBC/ ESNP colloids with diameter % 16 nm and core diameter % 2 nm were non-toxic to cells up to 200 mg/mL and exhibit excellent colloidal stability in physiological condition (pH = 7)as well as in the presence of IgG model protein. More promisingly, they had the relaxivity ratio to be r 2 /r 1 = 1.5, which is significantly lower than PEG-coated SNPs with core diameter = 1.5-6 nm; further which is similar to those of Gd-DOTA T 1weighted contrast agents. These results suggest that aqueous Cat-MDBC/ESNP colloids could be a promising candidate for T 1weighted MRI contrast enhancement.

“…These values are close to those expected for individual USNPs; for example, r 1 = 10.7 mM -1 s -1 and r 2 /r 1 = 3.6 for commerciallyavailable Supravist (SHU-555C) 49 this concentration appears to be significantly lower than that (0.9-1.9 mM Fe) for the corresponding COOH-MDBC having pendant carboxylates. 24 These results are promising in that Cat-MDBC/USNP colloids hold a great potential as an effective T 1 contrast agent with prolonged colloidal stability in physiological conditions. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Further, the cluster-like colloids presented transverse relaxivity constant r 2 = 93.5 mM -1 s -1 , which is close to typical values of negative MRI contrast agents of clusters having SNPs with diameter ≈ 4 nm 51 (Figure 6d and 6e).…”

Section: Hela Cell Hek Cellmentioning

confidence: 96%

Mussel-Inspired Multidentate Block Copolymer to Stabilize Ultrasmall Superparamagnetic Fe₃O₄ for Magnetic Resonance Imaging Contrast Enhancement and Excellent Colloidal Stability

Ramrup

et al. 2015

Chem. Mater.

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Colloidal ultrasmall superparamagnetic iron oxide nanoparticles (USNPs) with better control of their surface chemistry have been considered as a biocompatible alternative to clinically-used gadolinium-based contrast agents for in vivo bright magnetic resonance imaging (MRI). Herein, we report a versatile mussel-inspired multidentate block copolymer strategy that allows for the stabilization of USNPs as promising MRI contrast agents with excellent colloidal stability. Wellcontrolled multidentate block copolymer with pendant multiple catechol groups (Cat-MDBC) is synthesized by a combination of controlled radical polymerization and post-modification methods. The Cat-MDBC proves to be effective to strongly anchor to USNP surfaces as well as provide optimal hydrophilic surfaces; thus, enabling the fabrication of aqueous Cat-MDBC/USNP colloids at single layers with diameter ≈20 nm through biphasic ligand exchange process. They exhibit excellent colloidal stability in broad pH range and physiological conditions; no significant protein adsorption; and great magnetic properties including relaxivity and in vitro MRI. Further comparison of Cat-MDBC with its corresponding catechol-based multidentate random copolymer suggests the importance of the architecture of multidentate polymeric ligands for USNP-based MRI diagnosis. P(OEOMA-co-tBMA) with DP = 25 for OEOMA units and DP = 31 for tBMA units and 2) hydrolytic cleavage of pendant t-butoxy groups of tBMA units to the corresponding P(OEOMAco-MAA) (i.e. COOH-MDRC). Next, similar to Cat-MDBC, well-controlled Cat-MDRC was synthesized by the carbodiimide-medicated coupling reaction of pendant COOH groups of COOH-MDRC with amino groups of dopamine. 1 H-NMR of the resultant Cat-MDRC shows the presence of pendant catechol groups at 6.3-6.7 ppm (e), pendant OEO moieties at 4.0 ppm (b) and 3.2-3.7 ppm, backbone methyl groups at 0.7-1.1 ppm (c, d), and terminal phenyl groups at 7.3 ppm (a). Similar to Cat-MDBC, the integral ratio of the peaks (b, c, d, and e) was used to determine the extent of coupling reaction to be >90% (Figure S10b). After the successful synthesis of Cat-MDRC, the similar procedure for biphasic ligand exchange was examined in aqueous solution at the mass ratio of Cat-MDRC/USNP = 5/1 wt/wt. Both DLS and TEM results suggest the formation of multimodal clusters of Cat-MDRC/USNP colloids with their average diameters to be 40 and 115 nm (Figure 6b and 6c). Further to see if the formation of large clusters is due to biphasic ligand exchange process, the conventional ligand exchange process was examined, where OA surface ligands were replaced with new Cat-MDRC ligands on USNPs in organic solution (chloroform/EtOH solvent mixture). The resulting Cat-MDBC/USNP colloids were dispersed in water, yielding clusters with the diameter to be 42.6 nm and large aggregates (diameter >1 µm) in aqueous solution (Figure S11 of DLS diagram). These results are different from the formation of single layered Cat-MDBC/USNP