Paramagnetic ultrasmall gadolinium oxide (Gd(2)O(3)) nanoparticles with particle diameters (d) of approximately 1 nm were synthesized by using three kinds of Gd(III) ion precursors and by refluxing each of them in tripropylene glycol under an O(2) flow. A large longitudinal relaxivity (r(1)) of water proton of 9.9 s(-1) mM(-1) was estimated. As a result, high contrast in vivo T(1) MR images of the brain tumor of a rat were observed. This large r(1) is discussed in terms of the huge surface to volume ratio (S/V) of the ultrasmall gadolinium oxide nanoparticles coupled with the cooperative induction of surface Gd(III) ions for the longitudinal relaxation of a water proton. It is found from the d dependence of r(1) that the optimal range of d for the maximal r(1), which may be used as an advanced T(1) MRI contrast agent, is 1-2.5 nm.
Mutational alterations of the PTEN gene located on chromosome 10q23.3 have been frequently observed in a variety of human malignancies, including glioblastoma, melanoma, prostate cancer and endometrial cancer. 1-7 PTEN mutations and allelic deletions at 10q23 appear to be late events in glioblastoma, melanoma and prostate cancer, while in thyroid and endometrial cancers, PTEN alterations are found at an early stage, such as endometrial hyperplasia and benign thyroid tumors. 4 -9 Frequent germline or somatic mutations of PTEN have also been found in patients with Cowden disease and Bannayan-Zonana syndrome, which are autosomal dominant disorders characterized by the formation of multiple benign tumors and increased risk of malignant breast and thyroid tumors. 10,11 The PTEN gene encodes a protein product which shares high homology in its N-terminal region with the cytoskeletal protein tensin and the secretary vesicle protein auxilin. 1,2 The PTEN protein also contains a structural motif for a dual-specificity protein phosphatase. 12 PTEN acts as a phospholipid phosphatase, dephosphorylating PIP 3 with specificity for the phosphate group at the D3 position of the inositol ring. 13 PIP 3 is a lipid second messenger produced by PI3-kinase and activates a variety of signaling effectors such as AKT kinase. The lipid phosphatase activity of PTEN is essential for its ability to inhibit tumorigenesis and growth inhibition. 14,15 In human tumor cells lacking wild-type PTEN or in PTEN-deficient mice, PIP 3 levels are increased, leading to enhanced phosphorylation and activation of the survivalpromoting factor AKT kinase, indicating that PTEN exerts its tumor-suppressor function by negatively regulating the antiapoptotic PI3-kinase/AKT signaling pathway. 16 In addition, in immortalized PTEN-deficient mouse embryonic fibroblasts, PTEN restored apoptosis induced by stimuli such as UV irradiation. 17 The role of PTEN as a tumor-suppressor has also been attributed to its ability to modulate cell-cycle progression and cell motility. Expression of wild-type PTEN in PTEN-null glioblastoma or renal cell carcinoma cells causes cell-cycle arrest in the G 1 phase, inhibits colony formation and suppresses tumorigenicity in nude mice. 18 Exogenous expression of PTEN in fibroblasts and a glioma cell line with mutant PTEN alleles also suppresses cell migration, integrin-mediated cell spreading and focal adhesion. 19
A facile one-pot synthesis of d-glucuronic acid-coated ultrasmall Ln(2)O(3) (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles is presented. Their water proton relaxivities were studied to address their possibility as a new potential MRI contrast agent. We focused on the d-glucuronic acid-coated ultrasmall Dy(2)O(3) nanoparticle because it showed the highest r(2) relaxivity among studied nanoparticles. Its performance as a T(2) MRI contrast agent was for the first time proved in vivo through its 3 T T(2) MR images of a mouse, showing that it can be further exploited for the rational design of a new T(2) MRI contrast agent at high MR fields.
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