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1.
Theranostics ; 11(15): 7589-7599, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158868

RESUMO

Rational: Interstitial brachytherapy (BT) is a promising radiation therapy for cancer; however, the efficacy of BT is limited by tumor radioresistance. Recent advances in materials science and nanotechnology have offered many new opportunities for BT. Methods: In this work, we developed a biomimetic nanotheranostic platform for enhanced BT. Core-shell Au@AuPd nanospheres (CANS) were synthesized and then encapsulated in platelet (PLT)-derived plasma membranes. Results: The resulting PLT/CANS nanoparticles efficiently evaded immune clearance and specifically accumulated in tumor tissues due to the targeting capabilities of the PLT membrane coating. Under endoscopic guidance, a BT needle was manipulated to deliver appropriate radiation doses to orthotopic colon tumors while sparing surrounding organs. Accumulated PLT/CANS enhanced the irradiation dose deposition in tumor tissue while alleviating tumor hypoxia by catalyzing endogenous H2O2 to produce O2. After treatment with PLT/CANS and BT, 100% of mice survived for 30 days. Conclusions: Our work presents a safe, robust, and efficient strategy for enhancing BT outcomes when adapted to treatment of intracavitary and unresectable tumors.


Assuntos
Materiais Biomiméticos/farmacologia , Plaquetas , Braquiterapia , Ouro/farmacologia , Nanopartículas Metálicas/uso terapêutico , Neoplasias Experimentais/radioterapia , Paládio/farmacologia , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células RAW 264.7
2.
Int J Radiat Oncol Biol Phys ; 111(2): 502-514, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34023423

RESUMO

PURPOSE: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT). METHODS AND MATERIALS: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or -depleting agents. Tumor growth was monitored as a readout of therapeutic response. Flow cytometry and RNA sequencing of mouse tumors and analysis of transcriptomic data sets from irradiated human cancers were used to examine the immunomodulatory effects of the different radiation schedules. RESULTS: In AT3-OVA tumors, radiation DPF rather than BED determined the ability of RT to evoke local antitumor CD8+ T cell responses and synergize with anti-PD-1 therapy. Natural killer cell-mediated control of irradiated tumors was more sensitive to radiation BED. Radiation-induced regulatory T cell (Treg) responses, which were detected in both mouse and human tumors, were a major factor underlying the differential activation of adaptive immunity by radiation DPF and the activity of natural killer cells during the early phase of response to RT. Targeted inhibition of Treg responses within irradiated tumors rescued and enhanced local tumor control by RT and permitted the generation of abscopal and immunologic memory responses, irrespective of radiation schedule. MC38 tumors did not support the induction of an amplified Treg response to RT and were highly vulnerable to its immunoadjuvant effects. CONCLUSIONS: Local radiation-induced Treg responses are influenced by radiation schedule and tumor type and are a critical determinant of the immunoadjuvant potential of RT and its ability to synergize with T cell-targeted immunotherapy.


Assuntos
Fracionamento da Dose de Radiação , Neoplasias Experimentais/radioterapia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa/efeitos da radiação , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Imunidade Inata/efeitos da radiação , Imunomodulação , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia
3.
Anticancer Res ; 41(5): 2321-2331, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952457

RESUMO

BACKGROUND/AIM: The mechanisms of galectin-1 in radioresistance may not only involve intracellular but also extracellular effects because galectin-1 can be secreted into the extracellular matrix. We, therefore, aimed to investigate the role of the galectin-1 tumor microenvironment on radiosensitivity in a murine tumor model. MATERIALS AND METHODS: Wild-type or stable galectin-1-down-regulated cancer cells (melanoma (B16F10) and lung cancer (LLC1)) were injected (subcutaneous injection) into wild-type or knockout (galectin-1, B cells, and T cells) mice that were subject to 0 or 8 Gy irradiation. RESULTS: Galectin-1-down-regulated B16F10 cells showed increased radiosensitivity when injected into galectin-1 knockout mice. Interestingly, radioresistance of wild-type LCC1 tumors was noted when injected into galectin-1 and B cell knockout mice. However, radiosensitization was observed in T cell knockout mice with wild-type LCC1 cells. CONCLUSION: The role of endogenous galectin-1 in radioresistance exists in cases without extracellular galectin-1. Extracellular galectin-1 requires endogenous galectin-1 to radiosensitize tumors in mice.


Assuntos
Galectina 1/genética , Neoplasias Experimentais/radioterapia , Tolerância a Radiação/genética , Microambiente Tumoral/efeitos da radiação , Animais , Linhagem Celular Tumoral , Galectina 1/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Análise de Sobrevida , Carga Tumoral/genética , Carga Tumoral/efeitos da radiação , Microambiente Tumoral/genética
4.
Theranostics ; 11(13): 6293-6314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995659

RESUMO

Radioimmunotherapy (RIT) is FDA-approved for the clinical management of liquid malignancies, however, its use for solid malignancies remains a challenge. The putative benefit of RIT lies in selective targeting of antigens expressed on the tumor surface using monoclonal antibodies, to systemically deliver cytotoxic radionuclides. The past several decades yielded dramatic improvements in the quality, quantity, recent commercial availability of alpha-, beta- and Auger Electron-emitting therapeutic radiometals. Investigators have created new or improved existing bifunctional chelators. These bifunctional chelators bind radiometals and can be coupled to antigen-specific antibodies. In this review, we discuss approaches to develop radiometal-based RITs, including the selection of radiometals, chelators and antibody platforms (i.e. full-length, F(ab')2, Fab, minibodies, diabodies, scFv-Fc and nanobodies). We cite examples of the performance of RIT in the clinic, describe challenges to its implementation, and offer insights to address gaps toward translation.


Assuntos
Radioimunoterapia/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Quelantes/administração & dosagem , Quelantes/metabolismo , Química Click , Ensaios Clínicos como Assunto , Fracionamento da Dose de Radiação , Sistemas de Liberação de Medicamentos , Previsões , Humanos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Linfoma não Hodgkin/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Especificidade de Órgãos , Medicina de Precisão , Tolerância a Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Anticorpos de Cadeia Única/administração & dosagem , Anticorpos de Cadeia Única/uso terapêutico , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/uso terapêutico , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/uso terapêutico
5.
Int J Radiat Oncol Biol Phys ; 111(1): 240-248, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33845146

RESUMO

PURPOSE: Delivery of radiation at ultrahigh dose rates (UHDRs), known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared with tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypotheses being that the effect is related to substantial oxygen depletion upon FLASH, thereby altering the radiochemical damage during irradiation, leading to different radiation responses of normal and tumor cells. Testing of this hypothesis would be advanced by direct measurement of tissue oxygen in vivo during and after FLASH irradiation. METHODS AND MATERIALS: Oxygen measurements were performed in vitro and in vivo using the phosphorescence quenching method and a water-soluble molecular probe Oxyphor 2P. The changes in oxygen per unit dose (G-values) were quantified in response to irradiation by 10 MeV electron beam at either UHDR reaching 300 Gy/s or conventional radiation therapy dose rates of 0.1 Gy/s. RESULTS: In vitro experiments with 5% bovine serum albumin solutions at 23°C resulted in G-values for oxygen consumption of 0.19 to 0.21 mm Hg/Gy (0.34-0.37 µM/Gy) for conventional irradiation and 0.16 to 0.17 mm Hg/Gy (0.28-0.30 µM/Gy) for UHDR irradiation. In vivo, the total decrease in oxygen after a single fraction of 20 Gy FLASH irradiation was 2.3 ± 0.3 mm Hg in normal tissue and 1.0 ± 0.2 mm Hg in tumor tissue (P < .00001), whereas no decrease in oxygen was observed from a single fraction of 20 Gy applied in conventional mode. CONCLUSIONS: Our observations suggest that oxygen depletion to radiologically relevant levels of hypoxia is unlikely to occur in bulk tissue under FLASH irradiation. For the same dose, FLASH irradiation induces less oxygen consumption than conventional irradiation in vitro, which may be related to the FLASH sparing effect. However, the difference in oxygen depletion between FLASH and conventional irradiation could not be quantified in vivo because measurements of oxygen depletion under conventional irradiation are hampered by resupply of oxygen from the blood.


Assuntos
Neoplasias Experimentais/radioterapia , Oxigênio/análise , Animais , Camundongos , Neoplasias Experimentais/metabolismo , Consumo de Oxigênio , Dosagem Radioterapêutica
6.
Exp Cell Res ; 398(2): 112385, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33212146

RESUMO

Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the world. Radiotherapy is one of the standard therapies for patients with OSCC, but its clinical efficiency is limited due to radioresistance. In this study, we identified a mechanism of such resistance regulated by Ubiquitin-specific protease 14 (USP14). USP14 expression was significantly increased in clinical OSCC tissue samples and cell lines, and OSCC patients with high USP14 expression predicted poor overall survival rate. Additionally, a negative correlation between USP14 and LC3B was observed in patients with OSCC. We then found that irradiation (IR)-reduced cell survival of OSCC cells lines was further decreased when USP14 was knocked down. However, USP14 over-expression significantly promoted the cell viability of OSCC cells after IR treatment. Colony formation analysis confirmed thatafter IR treatment,USP14 knockdown markedly decreased the proliferation of OSCC cells, but over-expressing USP14 significantly up-regulated the proliferative activity of OSCC cells. Furthermore, DNA damage caused by IR was enhanced by USP14 knockdown, while been suppressed in OSCC cells with USP14 over-expression. Additionally, IR-inducedapoptosis was further promoted by USP14 knockdown in OSCC cells, which was, however, significantly abolished by USP14 over-expression.Moreover, our in vivo studies showed that IR-reduced tumor growth and tumor weight were further enhanced by USP14 knockdown in OSCC tumor-bearing nude mice. Finally, we found that USP14 knockdown could promote IR-induced autophagy by increasing LC3BII and γH2AX expression levels in IR-treated OSCC cells. However, this event was markedly abolished by ATG5 knockdown, subsequently restoring the cell proliferation in IR-incubated OSCC cells.Finally, we found that USP14-mediated apoptosis was autophagy-dependent in IR-treated OSCC cells. Taken together, these findings suggested that suppressing USP14 could alleviateradioresistancein OSCC both in vitro and in vivo by inducing apoptosis and autophagy, and thus could be served as a promising therapeutic strategy for OSCC treatment.


Assuntos
Autofagia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Apoptose , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Proliferação de Células , Sobrevivência Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/patologia , Neoplasias Bucais/radioterapia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/radioterapia , Células Tumorais Cultivadas
7.
Int J Nanomedicine ; 15: 3843-3850, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581534

RESUMO

Purpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Háfnio/farmacologia , Óxidos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Disponibilidade Biológica , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Feminino , Háfnio/química , Háfnio/farmacocinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Óxidos/química , Óxidos/farmacocinética
8.
J Cancer Res Ther ; 16(2): 203-208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474502

RESUMO

Objective: The objective of the study was to investigate the radiation damage to125 I seeds implanted in canine gastric wall tissue. Materials and Methods: Eight beagles were randomly assigned to either the treatment or control group, with four beagles per group. For each beagle in the treatment group, six125 I seeds were implanted in the gastric wall in two rows, spaced at 1.0 cm, with a seed activity of 0.5 mCi and a half-life of 60.2 d. For each beagle in the control group, six 125 I seeds were similarly implanted as a cold source. After implantation, the beagles were scanned by computed tomography (CT) (slice thickness: 2 mm), the region of interest was labeled along the seed boundaries, and postoperative doses were verified. One beagle per group was sacrificed at the 1, 2, 3, and 4 half-lives to be used as gross specimens for observing histological and ultrastructural changes using light microscopy and electron microscopy, respectively. Results: Beagles from the treatment group who had125 I radioactive seeds implanted in their stomach walls had the most radiation damage after two half-lives, damage repair began after three half-lives, and the damage was stabilized and further repaired after four half-lives. In the control group, only mild inflammatory reactions were observed around the seeds. Conclusion: Appropriate and well-planned implantation of125 I radioactive seeds in beagle stomach walls is safe and reliable.


Assuntos
Braquiterapia/efeitos adversos , Radioisótopos do Iodo/farmacologia , Neoplasias Experimentais/radioterapia , Lesões por Radiação/patologia , Estômago/patologia , Tomografia Computadorizada por Raios X/veterinária , Animais , Braquiterapia/métodos , Modelos Animais de Doenças , Cães , Feminino , Meia-Vida , Masculino , Neoplasias Experimentais/patologia , Lesões por Radiação/etiologia , Dosagem Radioterapêutica , Estômago/efeitos da radiação
9.
ACS Appl Mater Interfaces ; 12(11): 12395-12406, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32077680

RESUMO

We designed and synthesized 131I-labeled dendrimers modified with the LyP-1 peptide as a multifunctional platform for single-photon emission computed tomography (SPECT) imaging, radionuclide therapy, and antimetastasis therapy of cancer. The multifunctional platform was constructed by modifying amine-terminated generation 5 poly(amidoamine) dendrimers with 33.1 LyP-1 peptide and 9.2 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), followed by acetylation of the remaining dendrimer terminal amines and radiolabeling with 131I via the HPAO moieties. The LyP-1-modified dendrimers showed favorable cytocompatibility in the studied concentration range of 0.1-10 µM for 24 h and could be labeled by 131I with satisfactory radiochemical purity (>99%) and stability (>90% even at 16 h). The 131I-labeled LyP-1-modified dendrimers were capable of being utilized as a diagnostic probe for SPECT imaging and as a therapeutic agent for radionuclide therapy and antimetastasis of cancer cells in vitro and in a subcutaneous tumor model in vivo. Based on analyses of the tumor microenvironment, the antitumor and antimetastasis effects could be because of the reduced levels of the molecular markers associated with proliferation and metastasis, improved local hypoxia, and increased apoptosis rate. The developed 131I-labeled dendrimeric nanodevice may hold great promise to be used as a nanotheranostic platform for cancer diagnosis and therapy.


Assuntos
Antineoplásicos , Dendrímeros/química , Metástase Neoplásica , Peptídeos Cíclicos/química , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Radioisótopos do Iodo/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Radioisótopos/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos
10.
Phys Med ; 69: 256-261, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918378

RESUMO

PURPOSE: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator. METHODS: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls. RESULTS: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat's head and in a digital model of a rat's head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant. CONCLUSIONS: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Neoplasias Experimentais/radioterapia , Radiometria/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Modelos Animais de Doenças , Elétrons , Glioma/tratamento farmacológico , Íons , Estimativa de Kaplan-Meier , Masculino , Método de Monte Carlo , Neoplasias Experimentais/diagnóstico por imagem , Distribuição Normal , Prótons , Dosagem Radioterapêutica , Ratos , Ratos Endogâmicos F344 , Reprodutibilidade dos Testes , Síncrotrons , Resultado do Tratamento
11.
J Cell Physiol ; 235(1): 185-193, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190335

RESUMO

Cervical cancer (CC) is a prevalent malignancy in women, with the feature of metastasis and easy recurrence is responsible for a large proportion of global cancer deaths. Radiotherapy is one of the common treatment tools for CC patients with unresectable tumors. However, radio-resistance in patients could be a major reason for recurrence. Therefore, it is of significance to tunnel the molecular mechanism of radio-resistance in CC. MicroRNAs (miRNAs) are increasingly reported in the regulation of cancer progression and cellular response to radiotherapy and chemotherapy. miR-4429 is a newly discovered miRNA acting as a tumor-suppressor gene in multiple cancers, but its function in CC has never been explored yet. The current study tried to explore the role of miR-4429 in cell radio-sensitivity in CC. First, we validated the downregulation of miR-4429 in CC cells. Importantly, the association of miR-4429 with radio-resistance was validated by identifying the downregulation of miR-4429 in radio-resistant CC cells. Gain- and loss-of-function assays validated that miR-4429 sensitized CC cells to irradiation. Through bioinformatics tools, RAD51 recombinase (RAD51) was identified to be a target for miR-4429. RAD51 is known to be a crucial regulator for DNA damage repair and has been reported to influence cell radio-resistance in cancers, including in CC. Luciferase reporter assay confirmed the interaction between miR-4429 and RAD51. Finally, rescue assays indicated that miR-4429 promoted CC cell radio-sensitivity through RAD51. Consequently, our study showed that miR-4429 sensitized CC cells to irradiation by targeting RAD51, providing a potential therapeutic target for CC patients.


Assuntos
MicroRNAs/metabolismo , Rad51 Recombinase/metabolismo , Neoplasias do Colo do Útero/radioterapia , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Neoplasias Experimentais/radioterapia , Rad51 Recombinase/genética , Regulação para Cima
12.
Nanomedicine ; 23: 102084, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454552

RESUMO

Although chemically synthesized ferro/ferrimagnetic nanoparticles have attracted great attention in cancer theranostics, they lack radio-enhancement efficacy due to low targeting and internalization ability. Herein, we investigated the potential of RGD-tagged magnetosomes, bacterial biogenic magnetic nanoparticles naturally coated with a biological membrane and genetically engineered to express an RGD peptide, as tumor radioenhancers for conventional radiotherapy and proton therapy. Although native and RGD-magnetosomes similarly enhanced radiation-induced damage to plasmid DNA, RGD-magnetoprobes were able to boost the efficacy of radiotherapy to a much larger extent than native magnetosomes both on cancer cells and in tumors. Combined to magnetosomes@RGD, proton therapy exceeded the efficacy of X-rays at equivalent doses. Also, increased secondary emissions were measured after irradiation of magnetosomes with protons versus photons. Our results indicate the therapeutic advantage of using functionalized magnetoparticles to sensitize tumors to both X-rays and protons and strengthen the case for developing biogenic magnetoparticles for multimodal nanomedicine in cancer therapy.


Assuntos
Magnetossomos/química , Magnetospirillum/química , Neoplasias Experimentais/radioterapia , Oligopeptídeos , Radiossensibilizantes , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Terapia com Prótons , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Terapia por Raios X
13.
J Clin Invest ; 130(1): 466-479, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31815742

RESUMO

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.


Assuntos
Apresentação do Antígeno/efeitos da radiação , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Microbioma Gastrointestinal , Neoplasias Experimentais , Animais , Apresentação do Antígeno/genética , Antígenos de Neoplasias/genética , Butiratos/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Feminino , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/efeitos da radiação , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/radioterapia
14.
J Clin Invest ; 129(10): 4224-4238, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483286

RESUMO

Treatment of tumors with ionizing radiation stimulates an antitumor immune response partly dependent on induction of IFNs. These IFNs directly enhance dendritic cell and CD8+ T cell activity. Here we show that resistance to an effective antitumor immune response is also a result of IFN signaling in a different cellular compartment of the tumor, the cancer cells themselves. We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1. Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout. This enhanced response depended on CD8+ T cells and was mediated by enhanced susceptibility to T cell-mediated killing. Induction of Serpinb9 proved to be the mechanism underlying control of susceptibility to T cell killing after radiation. Ifnar1-deficient tumors had an augmented response to anti-PD-L1 immunotherapy with or without radiation. We conclude that type I IFN can protect cancer cells from T cell-mediated cytotoxicity through regulation of Serpinb9. This result helps explain why radiation of tumors can stimulate antitumor immunity yet also result in resistance. It further suggests potential targets for intervention to improve therapy and to predict responses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos da radiação , Interferon Tipo I/imunologia , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/radioterapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/radioterapia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Serpinas/genética , Serpinas/imunologia , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
15.
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
16.
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 , Imageamento por Ressonância Magnética/métodos , Animais , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Ratos , Ratos Endogâmicos F344
17.
Eur Rev Med Pharmacol Sci ; 23(13): 5802-5814, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31298332

RESUMO

OBJECTIVE: The aberrant expression of long noncoding RNAs (lncRNAs) is involved in the molecular regulation of non-small cell lung cancer (NSCLC). This study aims to investigate the biological interaction of lnc-FAM201A and its downstream factors and their impacts on the radiotherapy response of NSCLC. PATIENTS AND METHODS: Quantitative Polymerase Chain Reaction (qPCR) was used to determine the expression of FAM201A in NSCLC tissues. The Chi-square tests explored the association between FAM201A level and the poor clinicopathological characteristics (including radioresistance) of NSCLC. Univariate and multivariate Cox proportional hazards regression analyses were used to evaluate various prognostic factors for overall survival (OS). The effect of FAM201A on OS was tested by the log-rank test. A549/SK-MES-1 cell lines transfected with short hairpin RNA (shRNA) were used to verify the promoting effects of FAM201A on radiotherapy resistance in vitro and in vivo. Cell apoptosis (analyzed by flow cytometry), cell proliferation (determined by Cell Counting Kit-8), and mice xenograft models were performed to confirm the results. The downstream targets of FAM201A were predicted by bioinformatics tools. Additionally, the Dual-luciferase reporter assay, qPCR, and Western blotting were performed to confirm their interaction. RESULTS: FAM201A was significantly upregulated in tissues obtained from NSCLC patients resistant to radiotherapy. Increased FAM201A expression was strongly associated with radioresistance and inferior survival in NSCLC, as demonstrated by clinical data. The silence of FAM201A could inhibit cell proliferation and further cell apoptosis of NSCLC cells under X-ray irradiation both in vitro and in vivo. Moreover, by competitively targeting miR-370, FAM201A elevated the epidermal growth factor receptor (EGFR) and the hypoxia-inducible factor 1alpha (HIF-1α) levels. After FAM201A knockdown, EGFR and HIF-1α were repressed with enhanced radiosensitivity. CONCLUSIONS: The interference of FAM201A impairs its suppression of miR-370, resulting in the upregulation of EGFR and HIF-1α and enhancement of radiosensitivity in NSCLC patients. Collectively, our results indicated that this regulatory axis might serve as a potential therapeutic target to increase the sensitivity of radiotherapy in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Células A549 , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Proliferação de Células , Modelos Animais de Doenças , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/radioterapia , RNA Longo não Codificante/genética , Tolerância a Radiação/genética , Análise de Regressão , Células Tumorais Cultivadas
18.
J Biomed Opt ; 24(7): 1-10, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31313539

RESUMO

Cerenkov radiation (CR) is the emission of UV-vis light generated by the de-excitation of the molecules in the medium, after being polarized by an excited particle traveling faster than the speed of light. When ß particles travel through tissue with energies greater than 219 keV, CR occurs. Tissues possess a spectral optical window of 600 to 1100 nm. The CR within this range can be useful for quantitative preclinical studies using optical imaging and for the in-vivo evaluation of Lu177-radiopharmaceuticals (ß-particle emitters). The objective of our research was to determine the experimental emission light spectrum of Lu177-CR and evaluate its transmission properties in tissue as well as the feasibility to applying CR imaging in the preclinical studies of Lu177-radiopharmaceuticals. The theoretical and experimental characterizations of the emission and transmission spectra of Lu177-CR in tissue, in the vis-NIR region (350 to 900 nm), were performed using Monte Carlo simulation and UV-vis spectroscopy. Mice Lu177-CR images were acquired using a charge-coupled detector camera and were quantitatively analyzed. The results demonstrated good agreement between the theoretical and the experimental Lu177-CR emission spectra. Preclinical CR imaging demonstrated that the biokinetics of Lu177-radiopharmaceuticals in the main organs of mice can be acquired.


Assuntos
Lutécio , Imagem Óptica/métodos , Radioisótopos , Compostos Radiofarmacêuticos , Animais , Partículas beta , Linhagem Celular Tumoral , Radiação Eletromagnética , Estudos de Viabilidade , Humanos , Lutécio/química , Lutécio/farmacocinética , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/radioterapia , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética
19.
ACS Nano ; 13(7): 8320-8328, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31241895

RESUMO

Gold nanoclusters have become promising radiosensitizers due to their ultrasmall size and robust ability to adsorb, scatter, and re-emit radiation. However, most of the previously reported gold nanocluster radiosensitizers do not have a precise atomic structure, causing difficulties in understanding the structure-activity relationship. In this study, a structurally defined gold-levonorgestrel nanocluster consisting of Au8(C21H27O2)8 (Au8NC) with bright luminescence (58.7% quantum yield) and satisfactory biocompatibility was demonstrated as a nanoradiosensitizer. When the Au8NCs were irradiated with X-rays, they produced reactive oxygen species (ROS), resulting in irreversible cell apoptosis. As indicated by in vivo tumor formation experiments, tumorigenicity was significantly suppressed after one radiotherapy treatment with the Au8NCs. In addition, compared with tumors treated with X-rays (4 Gy) alone, tumors treated with the nanosensitizer exhibited an inhibition rate of 74.2%. This study contributes to the development of atomically precise gold nanoclusters as efficient radiosensitizers.


Assuntos
Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Ouro/farmacologia , Levanogestrel/farmacologia , Nanopartículas/uso terapêutico , Compostos Organoáuricos/farmacologia , Radiossensibilizantes/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Ouro/química , Humanos , Levanogestrel/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/radioterapia , Imagem Óptica , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Tamanho da Partícula , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Organismos Livres de Patógenos Específicos , Propriedades de Superfície , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos
20.
Ther Deliv ; 10(6): 353-362, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31184544

RESUMO

Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.


Assuntos
Terapia por Captura de Nêutron de Boro/efeitos adversos , Neoplasias Bucais/radioterapia , Mucosite/diagnóstico , Neoplasias Experimentais/radioterapia , Lesões por Radiação/diagnóstico , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Terapia por Captura de Nêutron de Boro/métodos , Carcinógenos/toxicidade , Cricetinae , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/complicações , Mucosite/etiologia , Mucosite/prevenção & controle , Neoplasias Experimentais/induzido quimicamente , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Dosagem Radioterapêutica , Índice de Gravidade de Doença
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