RESUMO
Among the nanomaterials, rare sesquioxides (lanthanide oxides such as Lu2O3) are of interest due to their adequate thermal conductivity, excellent chemical stability, and high light output. The prostate-specific membrane antigen (PSMA) is an integral multifunctional protein overexpressed in various types of cancer cells. The radiolabeled PSMA inhibitor peptides (iPSMA) have demonstrated their usefulness as specific probes in the treatment and detection of a wide variety of neoplasms, mainly due to their high in vivo recognition by the PSMA protein. The objective of this research was to synthesize Lu2O3-iPSMA nanoparticles (NPs) and characterize their physicochemical properties before and after neutron activation, as well as to assess their biodistribution profile and in vitro potential to target cells overexpressing PSMA. The Lu2O3 NPs were synthesized by the precipitation-calcination method and conjugated to the iPSMA peptide using DOTA (1,4,7,10-tetraazocyclodecane-N,N',Nâ³,Nâ´-tetraacetic acid) as a linking agent. Results of the physicochemical characterization by FT-IR and UV-Vis spectroscopies, SEM, TEM, DLS, HRTEM, SAED, DSC-TGA, and X-ray diffraction indicated the formation of Lu2O3-iPSMA NPs (diameter of 29.98 ± 9.07 nm), which were not affected in their physicochemical properties after neutron activation. 177Lu2O3-iPSMA NPs showed high affinity (Kd = 5.7 ± 1.9 nM) for the PSMA protein, evaluated by the saturation assay on HepG2 hepatocellular carcinoma cells (PSMA-positive). The biodistribution profile of the nanosystem in healthy mice showed the main uptake in the liver. After irradiation, radioactive Lu2O3-iPSMA NPs exhibited radioluminescent properties, making the in vivo acquisition of their biodistribution, via optical imaging, possible. The results obtained from this research validate the execution of additional preclinical studies with the objective of evaluating the potential of the 177Lu2O3-iPSMA NPs for the targeted radiotherapy and in vivo imaging of tumors overexpressing the PSMA protein.
Assuntos
Nanopartículas , Neoplasias da Próstata , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Nêutrons , Óxidos , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição TecidualRESUMO
INTRODUCTION: Integrin αvß3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg-Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of αvß3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical. METHODS: High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E-[c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2. RESULTS: Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/µmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting αvß3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios. CONCLUSIONS: The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing αvß3 integrins.
Assuntos
Compostos Heterocíclicos com 1 Anel/química , Peptídeos Cíclicos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Radioisótopos de Gálio/uso terapêutico , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glioma/patologia , Glioma/radioterapia , Integrina alfaVbeta3/metabolismo , Camundongos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Tomografia por Emissão de Pósitrons , Radioquímica , Radiometria , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição TecidualRESUMO
Molecular imaging comprises non-invasive monitoring of functional and spatiotemporal processes at molecular and cellular levels in living systems. Advanced imaging techniques can monitor such processes. Peptide receptors over-expressed in tumours can be targeted by peptides conjugated to radionuclides, near-infrared fluorochromes, metallic nanoparticles or quantum dots for target-specific cancer imaging.
Assuntos
Imagem Molecular/métodos , Neoplasias/diagnóstico , Oligopeptídeos , Animais , Corantes Fluorescentes/química , Produtos do Gene tat/química , Produtos do Gene tat/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Imagem Molecular/tendências , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/tendências , Pontos Quânticos , Receptores de Peptídeos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada de Emissão de Fóton Único/tendênciasRESUMO
A multifunctional system of gold nanoparticles (AuNP) capped by the [Tyr(3)]Octreotide (TOC) peptide was prepared and characterized by transmission electron microscopy (TEM) and UV-Vis, infrared and fluorescence spectroscopy. AuNP and AuNP-TOC fluorescence emission spectra were obtained both in solution and in murine AR42J-tumor tissues. Results suggest that AuNP were functionalized with TOC through interactions with the N-terminal amine of the phenylalanine, the amide groups and possibly with the indole group of the tryptophan residue. The fluorescence analyses in tissue revealed a recognition of the AuNP-TOC conjugate for the neuroendocrine tumor because of the lower energy position of the fluorescence resonance (692 nm) with respect to that of the AuNP in the same tumoral tissue (684 nm). The emission band observed in the near-infrared region (692 nm) opens the possibility for AuNP-TOC use in bioimaging.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Octreotida/análogos & derivados , Animais , Linhagem Celular Tumoral , Composição de Medicamentos , Rim/metabolismo , Masculino , Camundongos , Camundongos Nus , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Transplante de Neoplasias , Neoplasias/diagnóstico , Neoplasias/metabolismo , Octreotida/química , Octreotida/farmacocinética , Ligação Proteica , Receptores de Somatostatina/metabolismo , Espectrometria de Fluorescência , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Propriedades de Superfície , Distribuição TecidualRESUMO
The radiolabelled monoclonal antibody anti-CD20 has the property of binding to the CD20 antigen expressed on the cell surface of B-lymphocytes, thus making it a useful tool in the treatment of non-Hodgkin's lymphoma. In this work, the event-by-event Monte Carlo code NOREC is used to calculate the single-event distribution function f(1)(z) in the cell nucleus using the beta spectra of the (188)Re and (131)I radionuclides. The simulated geometry consists of two concentric spheres representing the nucleus and the cell surface embedded in a semi-infinite water medium. An isotropic point source was placed on the cell surface to simulate the binding of the anti-CD20 labelled with either (188)Re or (131)I. The simulations were carried out for two combinations of cell surface and nucleus radii. A method was devised that allows one to calculate the contribution of betas of energy greater than 1 MeV, which cannot be simulated by the NOREC code, to the single-event distribution function. It is shown that disregarding this contribution leads to an overestimation of the frequency-mean specific energy of the order of 9-12%. In general, the antibody radiolabelled with (131)I produces single-event distribution functions that yield higher frequency-mean specific energies.
Assuntos
Anticorpos Monoclonais/química , Antígenos CD20/química , Radiometria/métodos , Núcleo Celular/metabolismo , Dano ao DNA , Humanos , Radioisótopos do Iodo/farmacologia , Modelos Estatísticos , Método de Monte Carlo , Radioisótopos/farmacologia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Rênio/farmacologiaRESUMO
Radiation synovectomy is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. The aim of this work was to examine the feasibility of preparing dysprosium-166 (166Dy)/holmium-166(166Ho) hydroxide macroaggregates ([166Dy]Dy/166Ho-HM) as an in vivo generator for radiation synovectomy evaluating whether the stability of 166Dy-HM and 166Ho-HM complexes is maintained when the daughter 166Ho is formed. The Monte Carlo (MCNP4B) theoretical depth dose profile for the in vivo [166Dy]Dy/166Ho generator system in a joint model was calculated and compared with that produced by 90Y, 153Sm and 166Ho. 166Dy was obtained by neutron irradiation of enriched 164Dy2O3 in a Triga Mark III reactor. Macroaggregates were prepared by reaction of [166Dy]DyCl3 with 0.5 M NaOH in an ultrasonic bath. [166Dy]Dy/166Ho-HM was obtained with radiochemical purity >99.5% and with the majority of particles in the 2-5 microm range. In vitro studies demonstrated that the radio-macroaggregates are stable in saline solution and human serum without a significant change in the particle size over 14 d, suggesting that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biological studies in normal rats demonstrated high retention in the knee joint even 7 d after [166Dy]Dy/166Ho-HM administration. The Monte Carlo (MCNP4B) theoretical depth dose profiles in a joint model, showed that the in vivo [166Dy]Dy/166Ho generator system would produce 25% and 50% less radiation dose to the articular cartilage and bone surface, respectively, than that produced by 90Y or pure 166Ho in a treatment with the same therapeutic dose to the synovium surface. Despite that 153Sm showed the best depth dose profile sparing doses to healthy tissues, the use of 166Dy could provide the advantage of being applied in patients that cannot be reached within a few hours from a nuclear reactor and to produce less radiation exposure to the medical personnel during the radiopharmaceutical administration.
Assuntos
Disprósio/farmacocinética , Hólmio/farmacocinética , Marcação por Isótopo/métodos , Articulações/metabolismo , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Artrite Reumatoide/radioterapia , Disprósio/química , Disprósio/isolamento & purificação , Disprósio/uso terapêutico , Estudos de Viabilidade , Hólmio/química , Hólmio/isolamento & purificação , Hólmio/uso terapêutico , Humanos , Artropatias/radioterapia , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/isolamento & purificação , Substâncias Macromoleculares/uso terapêutico , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Radioisótopos/química , Radioisótopos/isolamento & purificação , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/isolamento & purificação , Compostos Radiofarmacêuticos/uso terapêutico , Ratos , Distribuição TecidualRESUMO
The aim of this work was to synthesize [166Dy]Dy/166Ho-DTPA-Biotin to evaluate its potential as a new radiopharmaceutical for targeted radiotherapy. Dysprosium-166 (166Dy) was obtained by neutron irradiation of enriched 164Dy(2)O(3) in a Triga Mark III reactor. The labeling was carried out in aqueous media at pH 8.0 by addition of [166Dy]DyCl(3) to diethylenetriaminepentaacetic-alpha,omega-bis(biocytinamide) (DTPA-Biotin). Radiochemical purity was determined by high-performance liquid chromatography (HPLC) and TLC. The biological integrity of labeled biotin was studied evaluating its avidity for avidin in an agarose column and by size-exclusion HPLC analysis of the radiolabeled DTPA-Biotin with and without the addition of avidin. Stability studies against dilution were carried out by diluting the radiocomplex solution with saline solution and with human serum at 37 degrees C for 24 h. The [166Dy]Dy/166Ho-labeled biotin was obtained with a 99.1+/-0.6% radiochemical purity. In vitro studies demonstrated that [166Dy]Dy/166Ho-DTPA-Biotin is stable after dilution in saline and in human serum and no translocation of the daughter nucleus occurs subsequent to beta(-) decay of 166Dy that could produce release of 166Ho(3+). Avidity of labeled biotin for avidin was not affected by the labeling procedure. Biodistribution studies in normal mice showed that the [166Dy]Dy/166Ho-DTPA-Biotin has a high renal clearance. In conclusion, the radiolabeled biotin prepared in this investigation has adequate properties to work as a stable in vivo generator system for targeted radiotherapy.
Assuntos
Biotina/análogos & derivados , Biotina/química , Disprósio/química , Hólmio/química , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Compostos Radiofarmacêuticos/química , Animais , Biotina/sangue , Biotina/farmacocinética , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Estabilidade de Medicamentos , Feminino , Injeções Intravenosas , Marcação por Isótopo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pentético/sangue , Ácido Pentético/farmacocinética , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
In this work we compare the Monte Carlo (MCNP4B) calculated beta-gamma depth-dose profile for a liquid 153Sm beta-gamma source used in radiation synovectomy with the experimental depth-dose distribution obtained using radiochromic dye film dosimetry. The calculated and experimental depth-dose distribution shows a very good agreement (within 5%) in the region where the dose deposition is dominated by the beta particle component (first 800 microm depth on tissue-equivalent material). The agreement worsens, reaching a maximum deviation of 15%, at depths close to the maximum range of the beta particles. Finally the agreement improves for the region where the gamma component accounts for one-third of the total absorbed dose (depths >1 mm). The possible contributions to these differences are discussed, as well as their relevance for the application of 153Sm in the treatment of rheumatoid arthritis.
Assuntos
Artrite Reumatoide/radioterapia , Partículas beta , Raios gama , Radioisótopos/uso terapêutico , Samário/uso terapêutico , Corantes , Humanos , Método de Monte Carlo , Radiometria/métodos , Dosagem Radioterapêutica , Reprodutibilidade dos TestesRESUMO
Infarct-avid radiopharmaceuticals are necessary for rapid and timely diagnosis of acute myocardial infarction. The animal model used to produce infarction implies artery ligation but chemical induction can be easily obtained with isoproterenol. A new infarct-avid radiopharmaceutical based on glucaric acid was prepared in the hospital radiopharmacy of the INCMNSZ. 99mTc-glucarate was easy to prepare, stable for 96 h and was used to study its biodistribution in rats with isoproterenol-induced acute myocardial infarction. Histological studies demonstrated that the rats developed an infarct 18 h after isoproterenol administration. The rat biodistribution studies showed a rapid blood clearance via the kidneys. Thirty minutes after 99mTc-glucarate administration the standardised heart uptake value S(h)UV was 4.7 in infarcted rat heart which is six times more than in normal rats. ROIs drawn over the gamma camera images showed a ratio of 4.4. The high image quality suggests that high contrast images can be obtained in humans and the 96 h stability makes it an ideal agent to detect, in patients, early cardiac infarction.
Assuntos
Ácido Glucárico/análogos & derivados , Isoproterenol/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/diagnóstico por imagem , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Animais , Cardiotônicos/efeitos adversos , Ácido Glucárico/síntese química , Ácido Glucárico/farmacocinética , Masculino , Compostos de Organotecnécio/farmacocinética , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos WistarRESUMO
In nuclear medicine radiation absorbed doses are important in the patient's risk/benefit evaluation and are estimated by means of biological and complex mathematical models. The biological model includes radiopharmacokinetic data obtained through blood and urine samples taken at given intervals. A useful mathematical model is the MIRD model and with the value for the time of residence tau the MIRDOSE3 computer program uses several anatomic models and calculates radiation absorbed dose for 25 organs. At the Radiopharmacy Unit of the Nuclear Medicine Department at INCMNSZ two new bone seeking radiopharmaceuticals, 99mTc-ABP and 188Re-ABP, have been designed, characterized and animal-tested. Radiopharmaceutical parameters and sequential scanning were obtained for diagnostic 99mTc-ABP in 10 normal subjects and the aim was to use % 24 hour urine elimination and % bone uptake to calculate radiation absorbed dose and extrapolate the values to 188Re-ABP as the basis for a therapeutic treatment. 99mTc-ABP was eliminated in women's urine 63.2 +/- 7.3%/activity and 70 +/- 11%/activity in men. In women 36.8 +/- 7.3% of the radiopharmaceutical remains on the bone surface and in men 30 +/- 11%. ROIs were drawn on the images and the time-integrated renal cpm/pixel/ROI gave a residence time tau = 0.52 h. Cumulative bone activity A calculated with A = 1.443 (T1/2) A0 was 2358 +/- 469 MBq h for women and 1923 +/- 707 MBq h for men. Residence time tau was 3.19 +/- 0.63 h in women and 2.6 +/- 0.95 h in men. Radiation absorbed dose for the whole body was 0.0020 +/- 0.0004 mGy/MBq for women and 0.0013 +/- 0.0005 mGy/MBq for men. For women's bone marrow it was 0.0063 +/- 0.0013 mGy/MBq and for men 0.0041 +/- 0.0015 mGy/MBq. 188Re-ABP behaves as 99mTc-ABP therefore, the effective dose given by 188Re, a beta emitter, would be for women 0.0936 mSv/MBq and for men 0.0608 mSv/MBq. These characteristics and the radionuclidic characteristics of 188Re indicate that 188Re-ABP might be a good bone metastases pain palliation radiopharmaceutical.