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Carbonic anhydrase IX (CAIX) is a transmembrane protein that is specifically overexpressed on the surface of hypoxic tumor cells. With the function of regulating the acidity of tumor cells both inside and outside, CAIX is closely related to tumor proliferation, invasion and metastasis. Therefore, CAIX is a promising target for tumor imaging and therapy. Herein, we summarized recent advances in CAIX-based tumor imaging, therapy and theranostics, and prospected future applications of using CAIX as an anti-tumor target.
Subject(s)
Carbonic Anhydrase IX , Carbonic Anhydrases/metabolism , Cell Line, TumorABSTRACT
Objective:To explore new methods of treating Graves′ disease (GD) by targeting thyroid stimulating hormone receptor (TSHR) and intercellular adhesion molecule-1 (ICAM-1).Methods:The small interfering RNA (siRNA) targeting TSHR and the ICAM-1 monoclonal antibody (mAb) were designed and synthesized. Thirty GD model mice were randomly divided into siRNA treatment group, ICAM-1 mAb treatment group, and untreated GD group (10 mice in each group), and 10 normal mice were taken as blank control. Serum thyroxine (T 4), thyroid stimulating hormone (TSH), TSH receptor-stimulating antibody (TSAb) and TSH-stimulation blocking antibody (TSBAb) were measured before and after treatment. At the end of the treatment, body mass and heart rate of mice in each group were measured, and thyroid uptake of 99Tc mO 4-, thyroid size and pathological changes were evaluated. Independent-sample t test, paired t test and one-way analysis of variance were used to analyze data. Results:After three treatments, the body mass of mice in siRNA group and ICAM-1 mAb group were significantly lower than that of normal mice ( F=3.50, P=0.025); the heart rates of the mice in two groups were significantly lower than that of untreated GD mice ( F=24.73, P<0.001). Heart rate of mice treated with siRNA decreased significantly, close to that of normal mice. After treatment, the serum T 4((27.58±1.94) vs (65.71±6.89) μg/L, (27.24±3.50) vs (70.84±8.46) μg/L), TSAb ((331.44±43.38) vs (457.33±45.85) mU/L, (275.16±45.80) vs (443.91±42.32) mU/L) and TSBAb ((13.94±1.11) vs (15.83±5.92) mU/L, (14.59±1.02) vs (17.05±6.16) mU/L) levels of mice in both siRNA group and ICAM-1 mAb group significantly decreased ( t values: 4.45-10.87, all P<0.05), while the serum TSH levels of mice in two groups significantly increased ((0.13±0.05) vs (0.04±0.05) mU/L, (1.46±0.34) vs (0.06±0.03) mU/L; t values: -2.22, -5.87, P values: 0.007, <0.001). The elevated TSH level and decreased TSAb level of mice treated with ICAM-1 mAb were significantly different from those treated with siRNA ( t values: 1.03, -1.63, P values: 0.002, 0.031). After treatment, the uptake of 99Tc mO 4- in part of the thyroid lobes of mice was decreased, and the enlargement degree of the corresponding lobes was reduced. The thyroid pathology of mice in the treated groups showed that the absorption vacuoles of thyroid follicles were reduced, and the phenomenon of thinner colloids was improved. No obvious damage was observed in the heart, liver and kidneys of the mice. Conclusions:Both the siRNA targeting TSHR and ICAM-1 mAb have therapeutic effects on GD model mice. The siRNA is better at controlling heart rate, and ICAM-1 mAb is better at increasing TSH and decreasing TSAb. Each of the above treatment methods is safe and effective, which can provide new ideas for GD targeted therapy.
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Objective To synthesize a new kind of acid-sensitive doxorubicin prodrug nanoparticles and to evaluate its anti-brain glioma effect and efficiency through blood-brain barrier (BBB). Methods The prodrug acid-sensitive poly-ethylene glycol (PEG)-doxorubicin (PEG-DOX) copolymer was synthesized by Schiff base reaction, and PEG-DOX pro-drug nanoparticles (PEG-DOX NPs) were prepared by self-assembling. The character of PEG-DOX copolymer was detected by dynamic light scattering (DLS) instrument and 1H NMR. The morphology of PEG-DOX NPs was observed by transmission electron microscopy (TEM). The character of drug release was detected by UV mothed. The cellular uptake efficiency of glio-ma cells to PEG-DOX NPs was observed by inverted fluorescence microscope. The anti-brain glioma effects of PEG-DOX NPs and Free DOX were studied by MTT mothed. PS80-PEG-DOX NPs were gained by the modification of PEG-DOX NPs with Tween 80. Nine BALB/c mice were separated into Free DOX, PEG-DOX NPs and PS80-PEG-DOX NPs groups by ran-dom drawing lots. The mean fluorescence intensity of brain and main organs were observed by in vivo imaging system. Re-sults The copolymer of PEG-DOX can self-assemble into nanoparticles with the diameter of 100 nm. PEG-DOX NPs can quickly release DOX in acid environment. Although PEG-DOX NPs had slow cancer cell uptake than Free DOX, it had lon-ger accumulation. MTT results showed that PEG-DOX NPs had concentration dependent anti-brain glioma effect. Indepen-dent samples t-test indicated that the efficiency through BBB was significantly higher in PS80-PEG-DOX NPs group than that of Free DOX group and PEG-DOX NPs group. Conclusion PEG-DOX NPs show well anti-brain glioma effect in vi-tro, and can across BBB with high efficiency after modification, which make it possible for a potential therapeutic prodrug for brain glioma.
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Objective To synthesize poly asparagine derivatives and to evaluate its safety at the cellular level, which provide research platform for its potential application as drug carrier. Methods Polysuccinimide was synthesized by ther?mal polymerization of L-polyaspartic acid, and the target product of PSI-Phe-EA was obtained by the ring-opening reaction of polysuccinimide using L-phenylalanine methyl ester hydrochloride and ethanol amine. The structure of PSI-Phe-EA were characterized by 1H NMR. The rate of ring-opening of PSI was calculated by internal standard method of 1H NMR. The change of hydrophilicity was studied by the comparison of solubility. The cytotoxicity and morphology modification by PSI-Phe-EA at designate concentrations was investigated by MTT method and inverted microscopy respectively. The effects on cell cycles were analyzed by flow cytometry after propidium iodide (PI) staining. Results 1H NMR results confirmed the structure of PSI-Phe-EA and the ring-openning rate of PSI was 40%. The hydrophilicity of PSI-Phe-EA was greatly in?creased upon ring opening using ethanol amine. MTT test showed that the cell survival rates of NIH 3T3 and HepG2 cells were higher than 80%under the examined concentration (<100 mg/L). Inverted microscopy showed that 50 mg/L of PSI-Phe-EA treatment had no adverse effects on cell morphology. Cell cycle analysis indicated that PSI-Phe-EA treatment had no in?fluence on cell cycles of NIH 3T3 and HepG2 cell lines. Conclusion PSI-Phe-EA showed high hydrophilicity without sig?nificant effects on the cells survival, cells morphology and cell cycles. It is a kind of safe polymer material.
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Objective To compare the biodistribution difference of peptide nanofibers, which were self-assembled by peptide composed of L-or D-amino acids, respectively, and provide the guidance for the in vivo applications of peptide nanofibers. Methods The Nap-GFFYGRGD (L-peptide) and Nap-GDFDFDYGRGD (D-peptide, F and Y were D-configura-tion) were synthesized with solid phase peptide synthesis (SPPS). The structure of the two peptides was identified by nuclear magnetic resonance spectroscopy (1H NMR) and high-resolution mass spectrometry (HR-MS). The two peptides could self-assemble into nanofibers during the cooling process after being boiled. The morphology of the nanofibers was observed with transmission electron microscope (TEM). The peptides were radiolabeled with iodine-125 and self-assembled into nanofi-bers, which were then administered into BALB/c mice via tail vein. The blood samples were collected and then mice were sacrificed at 1, 3, 6 and 12 hours. The main organs (heart, liver, spleen, lung, kidney, stomach, large intestine, small intes-tine, muscle and brain) were isolated and weighed. The radioactivity of organs was detected with a gamma counter. Results The two peptides could self-assemble into nanofibers with diameter of 10-20 nanometers. There were no significant differ-ences in the diameter and morphology between two naofibers. There was significant difference in the biodistribution between two nanofibers. The blood concentration of D-fiber was (8.17±0.32)%ID/g at one hour after injection and then cleared rapid-ly from the blood. The blood concentration of L-fiber was (5.96±0.30)%ID/g at one hour after injection and maintained at a stable level for six hours. The L-fiber was mainly distributed in stomach while the D-fiber was mainly accumulated in liver. Conclusion The configuration of amino acids (D/L) could affect the biodistribution of peptide nanofibers dramatically, which may provide the guidance for the medical applications of peptide nanofibers.