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1.
ACS Appl Mater Interfaces ; 11(31): 27536-27547, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31294958

RESUMO

Radiotherapy is a traditional method for cancer therapy but may become ineffective likely due to the radiation-induced immunosuppression. Instead of simply increasing the radiation dose, reactivation of immunosuppression in the tumor microenvironment is an alternative strategy for successful cancer treatment. In this work, we synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP). GLP-BiNP were able to increase the sensitivity of radiotherapy, attributing to the efficient X-ray absorption of bismuth element. BiNP alone can mildly activate dendritic cells (DC) in vitro, while GLP-BiNP further enhanced the level of DC maturation, shown as the increase in phenotypic maturation markers, cytokine release, acid phosphatase activity, and T cell proliferation in DC/T cell co-culture. Compared to BiNP, GLP-BiNP altered the tissue distribution with faster accumulation in the tumor. Meanwhile, mature DC greatly increased in both tumor and spleen by GLP-BiNP within 24 h. GLP-BiNP combination with radiation achieved remarkable inhibition of tumor growth through apoptosis. Alternatively, lung metastasis was largely prohibited by GLP-BiNP, shown as a reduced amount of tumor nodules and cancer cell invasion by pathological findings. Mechanistically, GLP-BiNP altered the tumor immunosuppression microenvironment by preferably increasing the number of intratumor CD8+ T cell proliferation, as well as the improved immunobalance shown as the increased serum interferon-γ/interleukin-4 ratio. Specifically, GLP conjugation seemed to protect the kidney from injury occasionally introduced by bare BiNP. As a result, GLP-BiNP play a dual role in tumor treatment through radiosensitization and immunoactivities.


Assuntos
Bismuto , Células Dendríticas/imunologia , Polissacarídeos Fúngicos , Nanopartículas , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Radiossensibilizantes , Reishi/química , Sulfetos , Animais , Bismuto/química , Bismuto/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Feminino , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/efeitos da radiação , Interferon gama/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/patologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Sulfetos/química , Sulfetos/farmacologia
2.
Neuroradiology ; 61(11): 1273-1280, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31297571

RESUMO

PURPOSE: To investigate the impact of blood-brain barrier (BBB) alterations induced by an experimental tumor and radiotherapy on MRI signal intensity (SI) in deep cerebellar nuclei (DCN) and the presence of gadolinium after repeated administration of a linear gadolinium-based contrast agent in rats. METHODS: Eighteen Fischer rats were divided into a tumor (gliosarcoma, GS9L model), a radiotherapy, and a control group. All animals received 5 daily injections (1.8 mmol/kg) of gadopentetate dimeglumine. For tumor-bearing animals, the BBB disruption was confirmed by contrast-enhanced MRI. Animals from the tumor and radiation group underwent radiotherapy in 6 fractions of 5 Gray. The SI ratio between DCN and brain stem was evaluated on T1-weigthed MRI at baseline and 1 week after the last administration. Subsequently, the brain was dissected for gadolinium quantification by inductively coupled plasma-mass spectrometry. Statistical analysis was done with the Kruskal-Wallis test. RESULTS: An increased but similar DCN/brain stem SI ratio was found for all three groups (p = 0.14). The gadolinium tissue concentrations (median, nmol/g) were 6.7 (tumor), 6.3 (radiotherapy), and 6.8 (control) in the cerebellum (p = 0.64) and 17.8/14.6 (tumor), 20.0/18.9 (radiotherapy), and 17.8/15.9 (control) for the primary tumor (p = 0.98) and the contralateral hemisphere (p = 0.41) of the cerebrum, respectively. CONCLUSION: An experimental brain tumor treated by radiotherapy or radiotherapy alone did not alter DCN signal hyperintensity and gadolinium concentration in the rat brain 1 week after repeated administration of gadopentetate. This suggests that a local BBB disruption does not affect the amount of retained gadolinium in the brain.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/efeitos da radiação , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Meios de Contraste/farmacocinética , Gadolínio DTPA/farmacocinética , Imagem por Ressonância Magnética/métodos , Animais , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Ratos , Ratos Endogâmicos F344
3.
PLoS One ; 14(2): e0212225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30768630

RESUMO

Tumour heterogeneity plays a large role in the response of tumour tissues to radiation therapy. Inherent biological, physical, and even dose deposition heterogeneity all play a role in the resultant observed response. We here implement the use of Haralick textural analysis to quantify the observed glycogen production response, as observed via Raman spectroscopic mapping, of tumours irradiated within a murine model. While an array of over 20 Haralick features have been proposed, we here concentrate on five of the most prominent features: homogeneity, local homogeneity, contrast, entropy, and correlation. We show that these Haralick features can be used to quantify the inherent heterogeneity of the Raman spectroscopic maps of tumour response to radiation. Furthermore, our results indicate that Haralick-calculated textural features show a statistically significant dose dependent variation in response heterogeneity, specifically, in glycogen production in tumours irradiated with clinically relevant doses of ionizing radiation. These results indicate that Haralick textural analysis provides a quantitative methodology for understanding the response of murine tumours to radiation therapy. Future work in this area can, for example, utilize the Haralick textural features for understanding the heterogeneity of radiation response as measured by biopsied patient tumour samples, which remains the standard of patient tumour investigation.


Assuntos
Raios gama , Neoplasias Experimentais/patologia , Neoplasias Experimentais/radioterapia , Análise Espectral Raman , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Camundongos
4.
Med Phys ; 46(2): 1030-1036, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30488962

RESUMO

PURPOSE: The goal of this work was to design a realistic mouse phantom as a useful tool for accurate dosimetry in radiobiology experiments. METHODS: A subcutaneous tumor-bearing mouse was scanned in a microCT scanner, its organs manually segmented and contoured. The resulting geometries were converted into a stereolithographic file format (STL) and sent to a multimaterial 3D printer. The phantom was split into two parts to allow for lung excavation and 3D-printed with an acrylic-like material and consisted of the main body (mass density ρ=1.18 g/cm3 ) and bone (ρ=1.20 g/cm3 ). The excavated lungs were filled with polystyrene (ρ=0.32 g/cm3 ). Three cavities were excavated to allow the placement of a 1-mm diameter plastic scintillator dosimeter (PSD) in the brain, the center of the body and a subcutaneous tumor. Additionally, a laser-cut Gafchromic film can be placed in between the two phantom parts for 2D dosimetric evaluation. The expected differences in dose deposition between mouse tissues and the mouse phantom for a 220-kVp beam delivered by the small animal radiation research platform (SARRP) were calculated by Monte Carlo (MC). RESULTS: MicroCT scans of the phantom showed excellent material uniformity and confirmed the material densities given by the manufacturer. MC dose calculations revealed that the dose measured by tissue-equivalent dosimeters inserted into the phantom in the brain, abdomen, and subcutaneous tumor would be underestimated by 3-5%, which is deemed to be an acceptable error assuming the proposed 5% accuracy of radiobiological experiments. CONCLUSIONS: The low-cost mouse phantom can be easily manufactured and, after a careful dosimetric characterization, may serve as a useful tool for dose verification in a range of radiobiology experiments.


Assuntos
Dosimetria Fotográfica/métodos , Neoplasias Experimentais/radioterapia , Imagens de Fantasmas , Radiobiologia , Planejamento da Radioterapia Assistida por Computador/métodos , Animais , Camundongos , Método de Monte Carlo , Órgãos em Risco/efeitos da radiação , Impressão Tridimensional , Dosagem Radioterapêutica
5.
Int J Nanomedicine ; 14: 8861-8874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32009784

RESUMO

Background: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models. Methods: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models. Results: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone. Conclusion: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.


Assuntos
Antracenos/química , Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Lewis/radioterapia , Nanopartículas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Antracenos/farmacocinética , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Disponibilidade Biológica , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Sistemas de Liberação de Medicamentos/métodos , Feminino , Raios gama , Humanos , Concentração de Íons de Hidrogênio , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Metiltransferases/metabolismo , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Polietilenoglicóis/química , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/farmacologia , Microambiente Tumoral
6.
ACS Appl Mater Interfaces ; 10(50): 43387-43395, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451482

RESUMO

Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible poly(lactide- co-glycolide)-monomethoxy-poly(polyethylene-glycol) (PLGA-mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with the previously reported boronated porphyrin drugs. Fluorescence imaging and positron emission tomography (PET) imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17 ± 13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumors to liver, muscle, fat, and blood were 3.24 ± 0.22, 61.46 ± 20.26, 31.55 ± 10.30, and 33.85 ± 5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT.


Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro , Neoplasias Experimentais , Imagem Óptica , Porfirinas , Tomografia por Emissão de Pósitrons , Animais , Boro/química , Boro/farmacocinética , Boro/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/radioterapia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia
7.
Immunity ; 49(3): 490-503.e4, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30170810

RESUMO

The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-κB pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-κB pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-κB pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.


Assuntos
Neoplasias do Colo/radioterapia , Células Dendríticas/imunologia , Melanoma/radioterapia , NF-kappa B/metabolismo , Neoplasias Experimentais/radioterapia , Radioterapia/métodos , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Neoplasias do Colo/imunologia , DNA/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Celular , Melanoma/imunologia , Melanoma Experimental , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Tolerância a Radiação , Radiação Ionizante , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Adv Exp Med Biol ; 1072: 189-194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178344

RESUMO

Tumor hypoxia is a major factor inducing resistance to radiotherapy. Spatial limitation in oxygen (O2) diffusion usually leads to chronic hypoxia, whereas temporary shut-down of perfusion or fluctuations in red blood cell flux can cause acute hypoxia. Since the role of temporal heterogeneity of pO2 in acute hypoxia during radiotherapy remains unclear, this study focuses on analyzing the influence of temporal heterogeneity of tumor hypoxia upon radiotherapy by modeling the temporal variance of acute hypoxia. The computational simulation was conducted on digital 2D tumor phantoms. The O2 diffusion and consumption within the tumor tissues were calculated using the reaction-diffusion equation. A total of nine experimental tumor lines (FaDu, GL, C3H, RIF, SCCVII, KHT, MEF, MTG, HT29) were modeled according to known pO2 distributions. Each tumor line was first simulated 36 times with various temporal heterogeneities (dynamic hypoxia) and once again without temporal heterogeneity (static hypoxia). Temporal pO2 fluctuations were modeled according to known red blood cell (RBC) fluxes. All tumor phantoms were irradiated with 30 fractions of 2 Gy. Cell survival was calculated as a function of pO2 and radiation dose via linear quadratic model. The simulation results indicate that the temporal heterogeneity varies with different tumor types, and tumor line HT29 shows the most significant impact of temporal heterogeneity upon the treatment effect. The ratio between the surviving fractions without and with temporal variance ranges from 1.44 to 6.28. Given the same mean pO2, the fraction of killed tumor cells in dynamic hypoxia is higher than in static hypoxia. A temporal heterogeneity index (THI) denoting normalized average pO2 temporal variance is proposed. The results show that for similar mean tumor pO2, a strong inverse correlation between THI and the surviving fraction is observed for each tumor line. THI is highly proportional to the fraction of acute hypoxia and to the RBC flux. The proposed THI corresponds well to the fraction of acute hypoxia.


Assuntos
Neoplasias Experimentais/patologia , Tolerância a Radiação/fisiologia , Hipóxia Tumoral/fisiologia , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Neoplasias Experimentais/radioterapia
9.
Strahlenther Onkol ; 194(10): 944-952, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29947818

RESUMO

BACKGROUND AND PURPOSE: Recently, imaging and high-precision irradiation devices for preclinical tumor models have been developed. Image-guided radiation therapy (IGRT) including innovative treatment planning techniques comparable to patient treatment can be achieved in a translational context. The study aims to evaluate magnetic resonance imaging/computed tomography (MRI/CT)-based treatment planning with different treatment techniques for high-precision radiation therapy (RT). MATERIALS AND METHODS: In an orthotopic pancreatic cancer model, MRI/CT-based radiation treatment planning was established. Three irradiation techniques (rotational, 3D multifield, stereotactic) were performed with the SARRP system (Small Animal Radiation Research Platform, Xstrahl Ltd., Camberley, UK). Dose distributions in gross tumor volume (GTV) and organs at risk (OAR) were analyzed for each treatment setting. RESULTS: MRI with high soft tissue contrast improved imaging of GTV and OARs. Therefore MRI-based treatment planning enables precise contouring of GTV and OARs, thus, providing a perfect basis for an improved dose distribution and coverage of the GTV for all advanced radiation techniques. CONCLUSION: An MRI/CT-based treatment planning for high-precision IGRT using different techniques was established in an orthotopic pancreatic tumor model. Advanced radiation techniques allow considering perfect coverage of GTV and sparing of OARs in the preclinical setting and reflect clinical treatment plans of pancreatic cancer patients.


Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Imagem por Ressonância Magnética/métodos , Neoplasias Experimentais/radioterapia , Neoplasias Pancreáticas/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Transplante de Neoplasias , Pesquisa Médica Translacional
10.
J Clin Invest ; 128(9): 3926-3940, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29952768

RESUMO

DNA-damaging chemotherapy and radiation therapy are integrated into the treatment paradigm of the majority of cancer patients. Recently, immunotherapy that targets the immunosuppressive interaction between programmed death 1 (PD-1) and its ligand PD-L1 has been approved for malignancies including non-small cell lung cancer, melanoma, and head and neck squamous cell carcinoma. ATR is a DNA damage-signaling kinase activated at damaged replication forks, and ATR kinase inhibitors potentiate the cytotoxicity of DNA-damaging chemotherapies. We show here that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate CD8+ T cell activity in mouse models of Kras-mutant cancer. Mechanistically, AZD6738 blocks radiation-induced PD-L1 upregulation on tumor cells and dramatically decreases the number of tumor-infiltrating Tregs. Remarkably, AZD6738 combines with conformal radiation therapy to generate immunologic memory in complete responder mice. Our work raises the possibility that a single pharmacologic agent may enhance the cytotoxic effects of radiation while concurrently potentiating radiation-induced antitumor immune responses.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos da radiação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Quimiorradioterapia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/radioterapia , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/imunologia , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacocinética , Radioterapia Conformacional , Sulfóxidos/farmacocinética
11.
Nanoscale ; 10(11): 5114-5123, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29487939

RESUMO

While radiotherapy (RT) is commonly used in clinics for cancer treatment, the therapeutic efficiency is not satisfactory owing to the existence of the hypoxic tumor microenvironment which seriously affects the efficiency of RT. Herein, we design polyethylene glycol (PEG)-modified reduced nano-graphene oxide-manganese dioxide (rGO-MnO2-PEG) nanocomposites to trigger oxygen generation from H2O2 to reduce the tumor hypoxic microenvironments. We use the radioisotope, 131I labeled rGO-MnO2-PEG nanocomposites as therapeutic agents for in vivo tumor radioisotope therapy (RIT), achieving excellent tumor killing and further enhancing the therapeutic efficiency of RIT. More importantly, the dissolution of MnO2 under acidic conditions and the redox process during the catalytic pathway of H2O2 decomposition in the cellular microenvironment direct to the production of an enormous amount of Mn2+ which has been used as a contrast agent for magnetic resonance imaging (MRI). Our proposed work provides a strategy to trigger oxygen formation via an internal stimulus to enhance imaging-guided RIT efficiency.


Assuntos
Grafite/química , Radioisótopos do Iodo/uso terapêutico , Compostos de Manganês/química , Nanocompostos/química , Neoplasias Experimentais/radioterapia , Óxidos/química , Hipóxia Tumoral , Animais , Linhagem Celular Tumoral , Feminino , Peróxido de Hidrogênio , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico por imagem
12.
Nanoscale ; 10(14): 6751-6757, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29589846

RESUMO

An unmet need in nanomedicine is to prepare biocompatible and renal clearable nanoparticles by controlling the diameter, composition and surface properties of the nanoparticles. This paper reports cellulose nanofiber templated synthesis of ultra-small bismuth nanoparticles, and their uses in enhanced X-ray radiation therapy. The interstitial spaces between adjacent fibers are the adsorption sites of bismuth ions and also stabilize nanoparticles generated by chemical reduction. The sizes of nanoparticles are tailored in the 2-10 nm range using cellulose nanofibers with various amounts of carboxyl groups. In vitro cytotoxicity, reactive oxygen species (ROS) and in vivo animal tests with tumor-bearing mice are studied in order to enhance X-ray radiation therapy using cellulose nanofiber-templated bismuth nanoparticles. Bismuth nanoparticles show strong X-ray attenuation ability, concentration-dependent cytotoxicity and high level production of ROS upon X-ray exposure, which is consistent with enhanced cellular damage and retarded growth of tumors in animals.


Assuntos
Bismuto/química , Celulose/química , Nanopartículas , Neoplasias Experimentais/radioterapia , Animais , Materiais Biocompatíveis , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanofibras , Espécies Reativas de Oxigênio/química , Propriedades de Superfície , Raios X
13.
Sci Rep ; 8(1): 1458, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29362374

RESUMO

Precise characterization of tumor recurrence and regrowth after radiotherapy are important for prognostic understanding of the therapeutic effect. Here, we established a novel in vivo mouse model for evaluating the characteristics of regrown tumor after repeated photon and carbon ion (C-ion) irradiations. The results showed that tumor growth rate, lung metastasis, shortening of the survival of the tumor-bearing mice, and tumor microvessel formation were promoted 2- to 3-fold, and expression of angiogenic and metastatic genes increased 1.5- to 15-fold in regrown tumors after repeated photon irradiations, whereas repeated C-ion irradiations did not alter these characteristics. Interestingly, both repeated photon and C-ion irradiations did not generate radioresistance, which is generally acquired for in vitro treatment. Our results demonstrated that the repetition of photon, and not C-ion, irradiations in vivo alter the characteristics of the regrown tumor, making it more aggressive without acquisition of radioresistance.


Assuntos
Neoplasias Pulmonares/secundário , Recidiva Local de Neoplasia/etiologia , Neoplasias Experimentais/radioterapia , Fótons/efeitos adversos , Animais , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Radioterapia com Íons Pesados/métodos , Camundongos
14.
Biochem Biophys Res Commun ; 495(4): 2566-2572, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29284117

RESUMO

BACKGROUND: Presence of unperfused regions containing cells under hypoxia and nutrient starvation contributes to radioresistance in solid human tumors. It is well known that hypoxia causes cellular radioresistance, but little is known about the effects of nutrient starvation on radiosensitivity. We have reported that nutrient starvation induced decrease of mTORC1 activity and decrease of radiosensitivity in an SV40-transformed human fibroblast cell line, LM217, and that nutrient starvation induced increase of mTORC1 activity and increase of radiosensitivity in human liver cancer cell lines, HepG2 and HuH6 (Murata et al., BBRC 2015). Knockdown of mTOR using small interfering RNA (siRNA) for mTOR suppressed radiosensitivity under nutrient starvation alone in HepG2 cells, which suggests that mTORC1 pathway regulates radiosensitivity under nutrient starvation alone. In the present study, effects of hypoxia and nutrient starvation on radiosensitivity were investigated using the same cell lines. METHODS: LM217 and HepG2 cells were used to examine the effects of hypoxia and nutrient starvation on cellular radiosensitivity, mTORC1 pathway including AMPK, ATM, and HIF-1α, which are known as regulators of mTORC1 activity, and glycogen storage, which is induced by HIF-1 and HIF-2 under hypoxia and promotes cell survival. RESULTS: Under hypoxia and nutrient starvation, AMPK activity and ATM expression were increased in LM217 cells and decreased in HepG2 cells compared with AMPK activity under nutrient starvation alone or ATM expression under hypoxia alone. Under hypoxia and nutrient starvation, radiosensitivity was decreased in LM217 cells and increased in HepG2 cells compared with radiosensitivity under hypoxia alone. Under hypoxia and nutrient starvation, knockdown of AMPK decreased ATM activity and increased radiation sensitivity in LM217 cells. In both cell lines, mTORC1 activity was decreased under hypoxia and nutrient starvation. Under hypoxia alone, knockdown of mTOR slightly increased ATM expression but did not affect radiosensitivity in LM217. Under hypoxia and nutrient starvation, HIF-1α expression was suppressed and glycogen storage was reduced. CONCLUSION: Our data suggest that AMPK regulates ATM expression and partially regulates radiosensitivity under hypoxia and nutrient starvation. The molecular mechanism underlying the induction of ATM expression by AMPK remains to be elucidated.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Hipóxia Celular/efeitos da radiação , Meios de Cultura/metabolismo , Regulação para Baixo/genética , Neoplasias Experimentais/radioterapia , Tolerância a Radiação , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular , Relação Dose-Resposta à Radiação , Regulação para Baixo/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Vetores Genéticos/genética , Células Hep G2 , Humanos , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Doses de Radiação , Vírus 40 dos Símios/genética , Transfecção
15.
Radiother Oncol ; 126(3): 471-478, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29269093

RESUMO

Many radiotherapy research centers have recently installed novel research platforms enabling the investigation of the radiation response of tumors and normal tissues in small animal models, possibly in combination with other treatment modalities. Many more research institutes are expected to follow in the coming years. These novel platforms are capable of mimicking human radiotherapy more closely than older technology. To facilitate the optimal use of these novel integrated precision irradiators and various small animal imaging devices, and to maximize the impact of the associated research, the ESTRO committee on coordinating guidelines ACROP (Advisory Committee in Radiation Oncology Practice) has commissioned a report to review the state of the art of the technology used in this new field of research, and to issue recommendations. This report discusses the combination of precision irradiation systems, small animal imaging (CT, MRI, PET, SPECT, bioluminescence) systems, image registration, treatment planning, and data processing. It also provides guidelines for reporting on studies.


Assuntos
Modelos Animais de Doenças , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Animais , Planejamento da Radioterapia Assistida por Computador/instrumentação , Radioterapia Guiada por Imagem/instrumentação
16.
Int J Radiat Oncol Biol Phys ; 100(2): 344-352, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29157749

RESUMO

PURPOSE: Specificity protein 1 (SP1) is involved in the transcription of several genes implicated in tumor maintenance. We investigated the effects of mithramycin A (MTA), an inhibitor of SP1 DNA binding, on radiation response. METHODS AND MATERIALS: Clonogenic survival after irradiation was assessed in 2 tumor cell lines (A549, UM-UC-3) and 1 human fibroblast line (BJ) after SP1 knockdown or MTA treatment. DNA damage repair was evaluated using γH2AX foci formation, and mitotic catastrophe was assessed using nuclear morphology. Gene expression was evaluated using polymerase chain reaction arrays. In vivo tumor growth delay was used to evaluate the effects of MTA on radiosensitivity. RESULTS: Targeting of SP1 with small interfering RNA or MTA sensitized A549 and UM-UC-3 to irradiation, with no effect on the BJ radiation response. MTA did not alter γH2AX foci formation after irradiation in tumor cells but did enhance mitotic catastrophe. Treatment with MTA suppressed transcription of genes involved in cell death. MTA administration to mice bearing A549 and UM-UC-3 xenografts enhanced radiation-induced tumor growth delay. CONCLUSIONS: These results support SP1 as a target for radiation sensitization and confirm MTA as a radiation sensitizer in human tumor models.


Assuntos
Dano ao DNA , Neoplasias Experimentais/radioterapia , Plicamicina/análogos & derivados , Radiossensibilizantes/farmacologia , Fator de Transcrição Sp1/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Humanos , Camundongos , Mitose/efeitos dos fármacos , Neoplasias Experimentais/patologia , Plicamicina/farmacologia
17.
Eur J Nucl Med Mol Imaging ; 45(1): 123-131, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28821931

RESUMO

PURPOSE: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. METHODS: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105. RESULTS: Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses. CONCLUSION: 177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Lutécio/química , Neoplasias Experimentais/radioterapia , Neovascularização Patológica/radioterapia , Radioimunoterapia/métodos , Radioisótopos/química , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Endoglina/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/patologia , Ácido Pentético/química , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
18.
Radiat Oncol ; 12(1): 174, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121984

RESUMO

BACKGROUND: To summarize the research activities of the "clinical research group heavy ion therapy", funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (12C-) ion- and photon irradiations. METHODS: Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either 12C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of 12C-ions was calculated from TCD50-values (dose at 50% tumor control probability) of photons and 12C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms. RESULTS: Experimental results revealed (i) a smaller variation of the TCD50-values between the three tumor sublines for 12C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for 12C-ions, and (iii) an RBE that increased with tumor grading (1.62 ± 0.11 (H) vs 2.08 ± 0.13 (HI) vs 2.30 ± 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD50, which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy. CONCLUSIONS: The dose-response studies revealed a higher efficacy of 12C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects.


Assuntos
Adenocarcinoma/radioterapia , Radioterapia com Íons Pesados , Fótons/uso terapêutico , Próstata/efeitos da radiação , Neoplasias da Próstata/radioterapia , Tolerância a Radiação , Animais , Carbono , Ciclo Celular , Diferenciação Celular , Relação Dose-Resposta à Radiação , Citometria de Fluxo , Hipóxia , Íons , Imagem por Ressonância Magnética , Masculino , Neoplasias Experimentais/radioterapia , Oxigênio , Tomografia por Emissão de Pósitrons , Ratos , Eficiência Biológica Relativa , Ultrassonografia Doppler
19.
Nanoscale ; 9(39): 14826-14835, 2017 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-28972612

RESUMO

Hypoxia and a dense extracellular matrix within the tumor microenvironment can often lead to the resistance of tumors to radiotherapy. Herein, we use bovine serum albumin (BSA) as a template to induce the growth of both gold (Au) nanoclusters and manganese dioxide (MnO2) via biomineralization. In the obtained BSA-Au-MnO2 composite nanoparticles, Au nanoclusters embedded within BSA not only show strong red fluorescence to facilitate imaging, but also act as a radio-sensitizer by absorbing and depositing X-ray energy within tumors to enhance radiotherapy. Meanwhile, the MnO2 core, which enables the formation of composite nanoparticles by connecting multiple albumins together, is able to modulate the tumor hypoxia by triggering the decomposition of tumor endogenous H2O2 into oxygen, so as to reverse the hypoxia-associated radiation resistance of tumors. Notably, such BSA-Au-MnO2 composite nanoparticles with larger sizes show prolonged blood circulation and increased tumor accumulation compared to BSA-Au complexes, and would dissociate back into individual BSA-Au complexes once inside the tumor with reduced pH to allow deep interstitial diffusion. As a result, highly effective radiotherapy of tumors is realized with these nanoparticles in a mouse tumor model. Our work thus presents a convenient biomineralization approach to fabricate intelligent multifunctional nanoparticles composed of biocompatible/biodegradable components for enhanced cancer therapy.


Assuntos
Nanopartículas Metálicas , Neoplasias Experimentais/radioterapia , Soroalbumina Bovina/química , Nanomedicina Teranóstica , Animais , Linhagem Celular Tumoral , Feminino , Ouro , Peróxido de Hidrogênio , Compostos de Manganês , Camundongos , Camundongos Nus , Células NIH 3T3 , Neoplasias Experimentais/diagnóstico por imagem , Óxidos
20.
Radiat Res ; 188(3): 335-341, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28686544

RESUMO

The purpose of this study was to compare the biological effects of fractionated doses versus a single dose of high-LET carbon ions in bystander normal cells, and determine the effect on their progeny using the layered tissue co-culture system. Briefly, confluent human glioblastoma (T98G) cells received a single dose of 6 Gy or three daily doses of 2 Gy carbon ions, which were then seeded on top of an insert with bystander normal skin fibroblasts (NB1RGB) growing underneath. Cells were co-cultured for 6 h or allowed to grow for 20 population doublings, then harvested and assayed for different end points. A single dose of carbon ions resulted in less damage in bystander normal NB1RGB cells than the fractionated doses. In contrast, the progeny of bystander NB1RGB cells co-cultured with T98G cells exposed to fractionated doses showed less damage than progeny from bystander cells co-cultured with single dose glioblastoma cells. Furthermore, inhibition of gap junction communication demonstrated its involvement in the stressful effects in bystander cells and their progeny. These results indicate that dose fractionation reduced the late effect of carbon-ion exposure in the progeny of bystander cells compared to the effect in the initial bystander cells.


Assuntos
Efeito Espectador/fisiologia , Efeito Espectador/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Fracionamento da Dose de Radiação , Fibroblastos/efeitos da radiação , Neoplasias Experimentais/radioterapia , Linhagem Celular , Sobrevivência Celular/fisiologia , Relação Dose-Resposta à Radiação , Fibroblastos/citologia , Fibroblastos/fisiologia , Radioterapia com Íons Pesados/métodos , Humanos , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Resultado do Tratamento
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