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

Design and development of amphiphilic block copolymer-based nanocarriers exhibiting enhanced colloidal stability upon dilution in the blood and cellular glutathione-responsive rapid drug release is highly desired for tumor-targeting chemotherapy. Herein, we report a novel ABA-type triblock copolymer consisting of a hydrophilic central poly(ethylene glycol) block and two terminal hydrophobic blocks of a polymethacrylate having pendant disulfides (PHMssEt), thus PHMssEt-b-PEG-b-PHMssEt (ssTP). Aqueous self-assembly and the following disulfide-exchange reaction of the resulting ssTP allow for formation of core-cross-linked micelles (CCMs) through the formation of new disulfide linkages, retaining enhanced colloidal stability in physiological conditions and in the presence of proteins. Further, they exhibit reduction-responsive enhanced release of encapsulated drugs in response to cellular concentrations of glutathione in cancer cells, confirmed by dynamic light scattering and spectroscopic analysis. Combined with these results, in vitro (cells) and in vivo (mouse model) biological results suggest that ssTP-based CCMs are effective candidates as intracellular nanocarriers targeting tumors for cancer therapy.

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.

Block copolymer-based magnetic nanoassembled structures with acidic cores exhibiting enhanced loading level of superparamagnetic iron oxide nanoparticles, thus having great potential for theranostics based on MRI.

The author name Dajana Vuckovic was incorrect in the original version. The spelling has been corrected above.