Shineng Luo

Enzyme-Controlled Intracellular Self-Assembly of 18F Nanoparticles for Enhanced MicroPET Imaging of Tumor

Herein, we report the development of a new “smart” radioactive probe (i.e., 1) which can undergo furin-controlled condensation and self-assembly of radioactive nanoparticles (i.e., 1-NPs) in tumor cells and its application for enhanced microPET imaging of tumors in nude mice co-injected with its cold analog (i.e., 1-Cold). Furin-controlled condensation of 1-Cold and self-assembly of its nanoparticles (i.e., 1-Cold-NPs) in vitro were validated and characterized with HPLC, mass spectra, SEM, and TEM analyses. Cell uptake studies showed that both 1 and 1-Cold have good cell permeability. TEM images of 1-Cold-treated MDA-MB-468 cells directly uncovered that the intracellular 1-Cold-NPs were at/near the location of furin (i.e., Golgi bodies). MTT results indicated that 50 µM 1-Cold did not impose cytotoxicity to MDA-MB-468 cells up to 12 hours. MicroPET imaging of MDA-MB-468 tumor-bearing mice indicated that mice co-injected with 1 and 1-Cold showed higher uptake and longer attenuation of the radioactivity in tumors than those mice only injected with same dosage of 1. Tumor uptake ratios of 1 between these two groups of mice reached the maximum of 8.2 folds at 240 min post injection. Biodistribution study indicated that the uptake ratios of 1 in kidneys between these two groups continuously increased and reached 81.9 folds at 240 min post injection, suggesting the formation of radioactive NPs (i.e., 1-NPs) in MDA-MB-468 tumors of mice co-injected with 1 and 1-Cold. And the nanoparticles were slowly digested and secreted from the tumors, accumulating in the kidneys. Our smart probe (i.e., 1), together with the strategy of co-injection, might help researchers trace the biomarkers of interest within a longer time window.

Dimethyl 5-amino-2,4,6-triiodo­isophthalate

The title compound, C(10)H(8)I(3)NO(4), crystallizes with two mol-ecules in the asymmetric unit. The I atoms and the benzene ring plane in the two mol-ecules are approximately coplanar, the I atoms deviating by -0.1631u2005(1), 0.0704u2005(1) and -0.0507u2005(1)u2005Å from the mean plane of the benzene ring in one mol-ecule and by 0.1500u2005(1), -0.0034u2005(1) and -0.1213u2005(1)u2005Å in the other. The planes of the ester groups are almost orthogonal to those of the benzene rings in both mol-ecules, forming dihedral angles of 83.5u2005(3), 76.4u2005(3), 97.3u2005(1) and 75.7u2005(1)°. The mean planes of the benzene rings in two mol-ecules are inclined at 69.8u2005(3)° with respect to each other. In the crystal, inter-molecular I⋯O inter-actions link the mol-ecules into infinite chains. In addition, N-H⋯O and non-classical C-H⋯O hydrogen bonds are observed.

Ethyl 3-carb-oxy-5-nitro-benzoate.

In the title compound, C10H9NO6, the carboxy, ethoxycarbonyl and nitro groups form dihedral angles of 3.8u2005(1), 4.5u2005(1) and 164.8u2005(1)°, respectively, with the mean plane of the benzene ring. In the crystal structure, molecules lying about inversion centers are linked through O—H⋯O hydrogen bonds. C—H⋯O interactions are also present.

Crystal structure of N-(2-hy-droxy-eth-yl)-5-nitro-isophthalamic acid monohydrate.

In the title compound, C10H10N2O6·H2O, the carboxylic acid group and the nitro group are essentially coplanar with the benzene ring [maximum deviation = 0.0264u2005(9)u2005Å], while the amide group is oriented at a dihedral angle of 9.22u2005(5)° with respect to the benzene ring. In the crystal, classical O—H⋯O and N—H⋯O hydrogen bonds and weak C—H⋯O interactions link the organic molecules and water molecules of crystallization into a three-dimensional supramolecular architecture.

3,4,6-Tri-O-acetyl-1,2-O-[1-(exo-ethoxy)ethylidene]-β-D-mannopyranose 0.11-hydrate.

The title compound, C(16)H(24)O(10)·0.11H(2)O, is a key intermediate in the synthesis of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), which is the most widely used molecular-imaging probe for positron emission tomography (PET). The crystal structure has two independent molecules (A and B) in the asymmetric unit, with closely comparable geometries. The pyranose ring adopts a (4)C(1) conformation [Cremer-Pople puckering parameters: Q = 0.553 (2) Å, θ = 16.2 (2)° and φ = 290.4 (8)° for molecule A, and Q = 0.529 (2) Å, θ =15.3 (3)° and φ = 268.2 (9)° for molecule B], and the dioxolane ring adopts an envelope conformation. The chiral centre in the dioxolane ring, introduced during the synthesis of the compound, has an R configuration, with the ethoxy group exo to the mannopyranose ring. The asymmetric unit also contains one water molecule with a refined site-occupancy factor of 0.222 (8), which bridges between molecules A and B via O-H···O hydrogen bonds.

Methyl 3-carboxy-5-nitrobenzoate

The structure of the title compound, C9H7NO6, is essentially planar [maximum deviation 0.284u2005(2)Å] except for the methyl H atoms. The crystal structure is stabilized by asymmetric O—H⋯O hydrogen bonds linking the hydrogen carboxylates into pairs around the inversion centres. There is also π–π stacking of the benzene rings [centroid–centroid distance 3.6912u2005(12)u2005Å].

3,5-Dinitro­benzoyl chloride

The carbonyl chloride group in the title compound, C7H3ClN2O5, is disordered over two orientations with occupancies of 0.505u2005(5) and 0.495u2005(5). The molecule is approximately planar, the dihedral angle between the carbonyl chloride plane and benzene ring being 9.6u2005(4)° in the major disorder component and 7.1u2005(4)° in the minor component. The nitro group at the 5-position is twisted, forming a dihedral angle of 6.7u2005(4)°. The crystal packing is stabilized by C—H⋯O hydrogen bonds.

4-(4-Ethoxy­benz­yl)-1,3-oxazolidin-2-one

In the title compound, C12H15NO3, the ethoxybenzyl ring plane forms a dihedral angle of 60.3u2005(4)° with the mean plane of the oxazolidine ring. The molecules are linked through N—H⋯O hydrogen bonds into a chain running in the b direction.

2-Isopropoxyphenyl N-methyl-carbamate.

In the title compound, C11H15NO3, the mean planes of the carboxamide and isopropyl groups are inclined at 109.9u2005(1) and 128.7u2005(2)°, respectively, to the mean plane of the phenoxy group. In the crystal structure, molecules are stacked along the b axis, without any π–π interactions. The stacked columns are linked together by intermolecular N—H⋯O hydrogen bonds, with an N⋯O distance of 2.842u2005(2)u2005Å.

Isobutyl 3,5-dinitro­benzoate

In the structure of the title compound, C11H12N2O6, the molecules are stacked along the b axis without any π–π interactions. The stacked columns are linked together by non-classical intermolecular C—H⋯O interactions,. In the molecule, the nitro groups make dihedral angles of 9.4u2005(5) and 10.3u2005(5)° with the benzene ring.