These nanoconstructs are composed of amphiphilic block copolymers with distinct hydrophobic and hydrophilic segments that can self-assemble into supramolecular core±shell structures (usually 10 to 100 nm) in aqueous solution. The hydrophobic micelle core provides an ideal carrier compartment for hydrophobic agents, and the shell consists of a protective corona that stabilizes the nanoparticles. Many hydrophobic drugs such as paclitaxel and doxorubicin have been successfully loaded inside the micelle core to improve drug solubility and pharmacokinetics. [2,3,6,7] In addition to therapeutic applications, polymeric micelles have also received increasing attention in diagnostic imaging applications. When incorporated into micelles, different types of contrast agents have achieved longer blood half-life, improved biocompatibility, and better contrast.[1]In this communication, we report the development of superparamagnetic polymeric micelles as a new class of magnetic resonance imaging (MRI) probes with remarkably high spin± spin (T 2 ) relaxivity and sensitivity. Superparamagnetic iron oxide (SPIO) nanoparticles such as magnetite (FeO´Fe 2 O 3 ) are known to have a strong effect on T 2 . Better detection sensitivity and slower kidney clearance of SPIO nanoparticles make them advantageous over Gd-based small molecular contrast agents. Currently, most T 2 contrast agents are composed of hydrophilic magnetite nanoparticles dispersed in a dextran matrix. [8,9] In contrast, our micelle design consists of a cluster of hydrophobic magnetite particles encapsulated inside the hydrophobic core of polymeric micelle whose surface is stabilized by a poly(ethylene glycol) (PEG) shell. This unique core±shell composite design has allowed us to achieve an ultrasensitive MRI detection limit of 5.2 lg mL ±1 (~5 nM), a sensitivity that promises to expand the ªtool boxº of MR probes for molecular imaging and image-visible drug-delivery applications.We used an amphiphilic diblock copolymer of poly(e-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) for the micelle formation (Fig. 1). This copolymer was synthesized by a ringopening polymerization of e-caprolactone using monomethoxy-terminated PEG (5 kDa; 1 Da .

A "smart" PARACEST MRI contrast agent was synthesized to detect caspase-3, which is an important biomarker in apoptosis. The well-known caspase-3 substrate, DEVD (Asp-Glu-Val-Asp), was elongated using the amino group on one sidearm of lanthanide ligand anchored on the polymer support. The amide of DEVD-(Tm-DOTA) showed a PARACEST effect with MR saturation at -51 ppm. DEVD-(Tm-DOTA) amide was successfully cleaved by caspase-3, exposing the free amine group, which showed PARACEST with saturation at +8 ppm. The enzymatic activity of caspase-3 can be detected by the change in PARACEST effect caused by this biotransformation.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use. K E Y W O R D APTw standardization, APT-weighted imaging, brain tumor, CEST imaging How to cite this article: Zhou J, Zaiss M, Knutsson L, et al. Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

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From the reactions between 2,2′-ethylidenebis(4,6-di-tert-butylphenol) and 2,2′-methylidenebis(4-dimethyl-6-di-tert-butylphenol) and Et 2AlCl the biphenoxide complexes [(O∼∼CHMe∼∼O)AlCl]2, 1, and [(O∼∼CH2∼∼O)AlCl]2, 2, have been isolated and characterized. These dimers are broken up by donor ligands, and the molecular structure of ethylidenebis(4,6-di-tert-butylphenoxide)AlCl(THF), 3, has been structurally characterized. Racemic 5,5′-6,6′-tetramethyl-3,3′-di-tert-butyl-1,1′-biphen-2,2′-diol and Et2AlCl react in hexane to give [(O∼∼O)AlCl]2, compound 6, as a hydrocarbon insoluble white precipitate. In the donor solvent THF monomeric species are formed, and (O∼∼O)AlX(THF) has been crystallographically characterized, X ) 20% Cl and 80% Et occupancy. Refluxing in THF favors X ) Cl, compound 4. The reaction of Et2Al(OEt) with the biphenol gives (O∼∼O)AlEt(THF), 5, in the presence of THF by displacement of one ethyl and one ethoxide ligand. Compounds 1, 2, 3, 4, 5, 6, [(O∼∼CHMe∼∼O)Al-(O i Pr-d7)]2, and [Cp2Zr(OEt)(OEt2)] + [HB(C6F5)3]act as propylene oxide, PO, polymerization catalyst precursors. The polymers have been examined by MS techniques and NMR spectroscopy, and these results are compared with polypropylene oxide, PPO, formed by base catalysis and by porphyrin-and salen-AlCl catalyst precursors. The new Al compounds and the cationic zirconium alkoxide give close to 50:50 HH to TT junctions with end groups C-Cl, OH, and )CH 2 being identified by MS and NMR. Polymerizations employing [(O∼∼CHMe∼∼O)Al(O i Pr-d7)]2 give HO-(PO)n-O i Pr-d7 oligomers, in addition to vinylterminated species. Polymerization of S-PO and 50:50 mixtures of S-PO and rac-PO reveals that the stereoirregular polymer is formed by a stereoselective ring-opening step. An analysis of the HH and TT junctions at the triad level is made, extending the earlier assignments of Tonelli and Schilling. This analysis leads us to suggest that polymerization occurs by a cationic coordinate mechanism wherein ring opening occurs by backside attack on an activated PO molecule which leads to inversion at the methine carbon. The rac-biphenoxide-Al complexes show a preference for ii and i linkages in (HT)(HT)(HT) units. These results are compared to coordinate catalysis polymerizations of PO employing the Union Carbide calcium amide-alkoxide system and (porphyrin)AlCl and lead us to predict that a cis-migratory ringopening polymerization process is not likely to be developed for polymerization of PO. † Dedicated to Dr. Walter Reichle, Corporate Research Fellow, Union Carbide, on the occasion of his retirement. * Corresponding author. E-mail Chisholm@chemistry. ohio-state.edu.