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Study on Preparation of SPIO Crosslinked with Octreotide and Differences of Its Uptake by SSTR Positive and Negative Tumor

Author: OuYangYang
Tutor: LiYiXiong
School: Central South University
Course: Surgery
Keywords: Carboxymethyl dextran The surface modification magnetic nanoparticles Octreotide acetate injection Superparamagnetic SPIO Somatostatin receptor - positive cells Somatostatin receptor -negative cells MRI
CLC: R73-3
Type: PhD thesis
Year: 2010
Downloads: 89
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Background somatostatin receptor positive cells were more common in neuroendocrine tumors (neuroendocrine an association between that NETs), it is a large class of tumor derived from neuroendocrine cells occur in the digestive system, but can be scattered occur multiple other organs in the human body . Its most important source of parts of the gastrointestinal and pancreatic (75 per cent), known as the gastrointestinal and pancreatic neuroendocrine tumors (gastroenteropancreatic neuroendocrine tumours, GEP NETs) aggressive surgical treatment is still the preferred method of GEP NETs. Lesions deep in the gastrointestinal wall or retroperitoneal, early diagnosis, accurate positioning difficult, thus affecting clinical outcomes. How can early diagnosis of neuroendocrine tumors and precise positioning to become the focus of research at home and abroad. Oncology research found that NETs on the cell membrane, have significantly high density distribution of somatostatin receptor (somatostatin receptor, SSTR). SSTR transmembrane receptor is a G-protein coupled membrane, there are five subtypes (SSTR1 - SSTR5), SSTR ligand is somatostatin (somatostatin, SST) currently referenced more somatostatin analogs (somatostatin analogues, SSTA). SSTA can and SSTR-specific binding and into the cell. SSTA as the function of the carrier, the by SSTR inner mechanism radioisotope taken to the cells, causing the tumor region radionuclide uptake by SPECT detected somatostatin receptor scintigraphy (somatostatin receptor scintigraphy, SRS ). SRS used in NETs primary tumors and metastases diagnosis, from the 1990s, had already begun research and clinical application, has gradually become a new inspection methods currently been widely carried out in a foreign country, but only in isotope scanning aspects. Surgery, need to know the precise spatial localization of the lesion and its relationship with the surrounding organs and tissues, and this is precisely the advantages of MRI. But the MRI not have the specificity and sensitivity of NETs. How can SRS complementary with the advantages of MRI to obtain a NETs both specificity and sensitivity, spatial resolution and high image, provides surgeons with a clear three-dimensional image, and clearly shows the lesion such a detection method of surrounding tissues and organs of the relationship between the direction we want to study. The purpose of this study is to superparamagnetic iron oxide contrast agent used in MRI detection (superparamagnetic iron oxide, SPIO) modified by chemical methods and achieve the coupling between and octreotide, a SPIO-octreotide complexes in octreotide Fe3O4 nanoparticles selectively into the SSTR-positive tumor cells, the formation of the selective aggregation of the of Fe3O4 particles within the cytoplasmic, local relaxation times of great change, underwent MRI scanning detection with SSTR specific receptor binding of this signal change and get the image that MR molecular imaging of somatostatin receptor (somatostatin receptor magnetic resonance molecular imaging, SRMRMI). We hope that both the specificity and sensitivity of the SRS SRMRMI, but also has a the MRI high image spatial resolution, and thus provide a new way of thinking for the early diagnosis and localization of somatostatin receptor positive tumors. The text is divided into two parts. Objective: To prepare high dispersion stability of nano level Carboxymethyldextran modified nano-Fe3O4 magnetic composite particles, made with Octreotide conjugated SPIO-octreotide coupled complex. Methods: Ultrasound pretreatment technology, in Carboxymethyldextran water dispersion system by chemical coprecipitation method carboxymethyl dextran surface modified nanoparticles, after octreotide on coupled with infrared spectroscopy (IR) The atomic force microscope (AFM), transmission electron microscopy (TEM), X-ray diffraction (XRD), oscillating sample magnetometer (VSM) product characterized. Results: (1) to the ferric chloride and ferrous chloride as the iron source, dextran, as modifier, and the reaction solution after ultrasonic pretreatment by chemical coprecipitation method was successfully prepared carboxymethyl dextran magnetic nano particles (CMD-MNPs). Via an amide bond octreotide to covalently connected to the top of the nanoparticles, the CMD-the MNPs-OC. (2) through the analysis of the scanning electron microscope of CMD-MNPs-Oc particles: the particle diameter of about 50nm, a narrow particle size distribution, showing a good spherical shape. The ultrasound pretreatment mixed solution can be a good block of Fe3O4 nanoparticles reunion. The modification of the dextran is not changed of Fe3O4 crystal structure, but also improves the water solubility and stability of the magnetic nanoparticles. (3) through the detection of the magnetization curve in the applied magnetic field, particles having superparamagnetic prove CMD-MNPs-Oc to 35emu · g-1, the saturation magnetization at room temperature. Conclusion: the dispersion of the composite nanoparticles prepared by ultrasound pretreatment better remains Fe3O4 crystalline structure. 2. Magnetic composite nanoparticles after carboxymethyl dextran-modified, in aqueous solution stability was significantly improved, and still having a superparamagnetic. The injection of superparamagnetic purpose: the detection of pancreatic cancer BXPC-3 cells with colon cancer HCT-116 cells somatostatin receptor subtypes expression to determine the somatostatin receptor-positive and-negative cell lines; somatostatin receptor positive tumor cells whether specific uptake of coupled octreotide SPIO-; detection coupled octreotide SPIO co-culture after somatostatin receptor-positive cells and somatostatin receptor-negative cells MRI signal differences. Method: BxPC-3 pancreatic cancer cells were cultured, HCT-116 colon cancer cells. Using RT-PCR to both intracellular SSTR1 of SSTR2 and SSTR3 SSTR4, SSTR5 mRNA expression were detected to determine the somatostatin receptor-positive and-negative tumor cell lines. Two cell lines routinely cultured to logarithmic phase, the same concentration CMD-MNPs-Oc solution were added to each medium, common culture, that is divided into two groups: A group CMD-MNPs-Oc after incubation of BxPC 3 cells; HCT-116 cells after incubation with group B CMD-MNPs-Oc. Then were taken in the same incubation time the cell suspension for cell sediment-line electron microscope examination, whether the observed Fe3O4 particles to be taken into tumor cells, and compare Fe3O4 particles in the distribution of parts and the amount of intracellular HE staining and Prussian blue staining two methods quantitative detection of Fe3O4 into the somatostatin positive tumor cells and somatostatin-negative tumor cells, the amount (grouped with electron microscopy). The treated cell suspension with the MRI machine for scanning, detecting Fe3O4 particles within the cell selective accumulation Chi relaxivity change (A, B packet with the electron microscopy, the C group was a pure culture of a cell-free liquid as blank). Results: RT-PCR results showed that BxPC-3 cells SSTR1 of SSTR2 and SSTR3,., SSTR4 SSTR5 showed positive expression, opposite HCT-116 cells showed negative expression. Electron microscopy results show that Fe3O4 particles enter the cells in group A, more and more in the cytoplasm rather than the mitochondria, and small pinocytotic visible bubble formation; Fe3O4 particles enter the cells in group B, few and located within the lysosomes. HE staining showed that BxPC-3 cells after incubation of the A group CMD-MNPs-Oc cytoplasmic see more scattered in the granular material, HCT-116 cells after the incubation of the B group CMD-MNPs-Oc no particles substance. A group BxPC-3 cells intracytoplasmic further Prussian blue staining showed more dark blue or cyan Fe3O4 particles, the percentage of positive cells was 97%, while the group B, HCT-116 cells intracytoplasmic rare deep blue , or cyan Fe3O4 particles, the percentage of positive cells in 6%. The results of MRI to detect cells in group A MRI scan T2-weighted image signal intensity was significantly lower than the signal of the blank control group (P lt; 0.001) in group C, the signal intensity decreased rate of 69.6%, the signal intensity was significantly lower than group B, the difference statistically significant (P lt; 0.001) Conclusion: 1. BxPC-3 cells, somatostatin receptor-positive expression, negative expression of somatostatin receptors in HCT-116 cells. 2. CMD-MNPs-Oc through receptor binding of Fe3O4 particles specific targeting is ingested into the somatostatin receptor-positive cytoplasmic. 3. CMD-MNPs-Oc by specifically targeting the Fe3O4 particles intake to somatostatin receptor-positive cytoplasmic enabling MRI detection of somatostatin receptor-positive cells and somatostatin receptor the significant difference of the signals of the body-negative cells.

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