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1.
Nat Commun ; 12(1): 769, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536445

RESUMO

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.


Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Metástase Neoplásica , Receptor de Morte Celular Programada 1/metabolismo
2.
Carbohydr Polym ; 254: 117476, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33357929

RESUMO

Herein the nucleic acid aptamers were attached to the polydeoxyadenylic acid (poly(dA)) tail for improving the tumor-targetability and cellular internalization of s-LNT/poly(dA) composite composed of two single chains of triple helical ß-glucan lentinan (s-LNT) and one poly(dA) chain. The in vitro results demonstrate that the cellular uptake of s-LNT/poly(dA) composites in MCF-7 cancer cells was enhanced effectively after attaching the aptamer. The as-prepared fluorescin isothiocyanate (FITC)-labelled LNT (LNT-FITC) through grafting was used for tracing the enhanced tumor-targetability of the composites. As a result, the cellular internalization of the LNT-FITC into MCF-7 and 4T1 cancer cells was further increased by the aptamer conjugated to poly(dA). Meanwhile, the in vivo experiments further demonstrate more s-LNT/poly(dA)-aptamer composites were effectively accumulated at the tumor site compared with s-LNT alone. This work provides a novel strategy for fabricating triplex ß-glucan as delivery vectors with active tumor-targetability.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/administração & dosagem , Lentinano/farmacologia , Neoplasias Mamárias Experimentais/terapia , Terapia de Alvo Molecular/métodos , Poli A/administração & dosagem , Animais , Antineoplásicos/química , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Linhagem Celular Tumoral , Portadores de Fármacos , Feminino , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Humanos , Injeções Intravenosas , Lentinano/química , Células MCF-7 , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Poli A/química , Poli A/genética , Coloração e Rotulagem/métodos
3.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33353068

RESUMO

Breast cancer is one of the most frequently diagnosed malignancies and common causes of cancer death in women. Recent studies suggest that environmental exposures to certain chemicals, such as 7,12-Dimethylbenzanthracene (DMBA), a chemical present in tobacco, may increase the risk of developing breast cancer later in life. The first-line treatments for breast cancer (surgery, chemotherapy or a combination of both) are generally invasive and frequently associated with severe side effects and high comorbidity. Consequently, novel approaches are strongly required to find more natural-like experimental models that better reflect the tumors' etiology, physiopathology and response to treatments, as well as to find more targeted, efficient and minimally invasive treatments. This study proposes the development and an in deep biological characterization of an experimental model using DMBA-tumor-induction in Sprague-Dawley female rats. Moreover, a photothermal therapy approach using a near-infrared laser coupled with gold nanoparticles was preliminarily assessed. The gold nanoparticles were functionalized with Epidermal Growth Factor, and their physicochemical properties and in vitro effects were characterized. DMBA proved to be a very good and selective inductor of breast cancer, with 100% incidence and inducing an average of 4.7 tumors per animal. Epigenetic analysis showed that tumors classified with worst prognosis were hypomethylated. The tumor-induced rats were then subjected to a preliminary treatment using functionalized gold nanoparticles and its activation by laser (650-900 nm). The treatment outcomes presented very promising alterations in terms of tumor histology, confirming the presence of necrosis in most of the cases. Although this study revealed encouraging results as a breast cancer therapy, it is important to define tumor eligibility and specific efficiency criteria to further assess its application in breast cancer treatment on other species.


Assuntos
5-Metilcitosina/metabolismo , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Hipertermia Induzida , Neoplasias Mamárias Experimentais/terapia , Nanopartículas Metálicas/administração & dosagem , Modelos Teóricos , Animais , Peso Corporal , Feminino , Ouro/química , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Nanopartículas Metálicas/química , Ratos , Ratos Sprague-Dawley
4.
Proc Natl Acad Sci U S A ; 117(38): 23684-23694, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907939

RESUMO

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3 -/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Mamárias Experimentais , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma/imunologia
5.
Int J Nanomedicine ; 15: 1409-1420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184595

RESUMO

Background: Photothermal therapy with accurate and real-time temperature detection is desired in clinic. Upconversion nanocrystals (UCNs) are candidate materials for simultaneous temperature detection and photothermal agents carrying. However, the weak luminescence and multiple laser excitations of UCNs limit their application in thermal therapy. Materials and Methods: NaYF4:Yb3+,Er3+,Nd3+, PL-PEG-NH2, IR-806 and folic acid are selected as structural components. A nanoprobe (NP) integrated with efficient photothermal conversion and sensitive temperature detection capabilities is synthesized for precise photothermal therapy. The probes are based on near-infrared upconversion nanocrystals doped with Yb, Er and Nd ions, which can be excited by 808 nm light. IR-806 dye molecules are modified on the surface as molecular antennas to strongly absorb near-infrared photons for energy transfer and conversion. Results: The results show that under an 808 nm laser irradiation upconversion luminescence of the nanocrystals is enhanced based on both the Nd ion absorption and the FRET energy transfer of IR-806. The luminescence ratio at 520 and 545 nm is calculated to accurately monitor the temperature of the nanoparticles. The temperature of the nanoprobes increases significantly through energy conversion of the molecular antennas. The nanoparticles are found successfully distributed to tumor cells and tumor tissue due to the modification of the biocompatible molecules on the surface. Tumor cells can be killed efficiently based on the photothermal effect of the NPs. Under the laser irradiation, temperature at mouse tumor site increases significantly, tissue necrosis and tumor cell death can be observed. Conclusion: Precision photothermal therapy can thus be achieved by highly efficient near-infrared light absorption and accurate temperature monitoring, making it promising for tumor treatment, as well as the biological microzone temperature detection.


Assuntos
Nanopartículas/química , Fototerapia/métodos , Termografia/métodos , Animais , Linhagem Celular Tumoral , Érbio/química , Feminino , Raios Infravermelhos , Lasers , Luminescência , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos BALB C , Neodímio/química , Temperatura , Itérbio/química , Ítrio/química
6.
Cancer Immunol Immunother ; 69(7): 1165-1175, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32130452

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy is a novel approved treatment for hematological malignancies, still under development for solid tumors. Here, we use a rate equation-based mathematical model to discover regimens and schedules that maintain efficacy while potentially reducing toxicity by decreasing the amount of CAR-T infused. Tested on an in vivo murine model of spontaneous breast cancer, we show that our mathematical model accurately recapitulates in vivo tumor growth results achieved in the previous experiments. Moreover, we use the mathematical model to predict results of new therapy schedules and successfully prospectively validated these predictions in the in vivo. We conclude that using one tenth and even one percent of a full CAR-T dose used in preclinical trials can achieve efficacious results similar to full dose treatment.


Assuntos
Modelos Animais de Doenças , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/normas , Neoplasias Mamárias Experimentais/terapia , Modelos Teóricos , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Feminino , Neoplasias Mamárias Experimentais/imunologia , Camundongos
7.
Life Sci ; 250: 117550, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179071

RESUMO

Breast cancer is the frequently diagnosed cancer among women and it is the most lethal malignancy in women globally. With one million cases every year, breast cancer is the fast-growing cancer type that has a high prevalence rate in young women. The limitations and undesirable side effects of conventional therapies like chemotherapy and radiotherapy on malignant tumors necessitate the development of alternative therapeutic approaches. Gene therapy has emerged as a promising approach to cure a variety of malignant cancer types which involves the delivery of functional gene directly into the target tumor tissue. Efficient gene therapy approach relies on the effective delivery of therapeutic genes to the desired cell type. In this regard, biological and non-biological gene delivery vectors are used to protect the naked foreign DNA to mediate effective tissue entry of the desired gene of interest. In this review, the use of bacterial and viral vectors for breast cancer gene therapy was summarized.


Assuntos
Bactérias , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Vetores Genéticos , Vírus , Animais , Feminino , Técnicas de Transferência de Genes , Terapia Genética/métodos , Humanos , Neoplasias Mamárias Experimentais/terapia , Transplante de Neoplasias , Vírus Oncolíticos , Prognóstico
8.
Biochim Biophys Acta Mol Basis Dis ; 1866(5): 165713, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32014550

RESUMO

BACKGROUND: Metabolomic strategies have been extensively used to search for biomarkers of disease, including cancer, in biological complex mixtures such as cells, tissues and biofluids. In breast cancer research, murine models are of great value and metabolomics has been increasingly applied to characterize tumor or organ tissues, or biofluids, for instance to follow-up metabolism during cancer progression or response to specific therapies. SCOPE OF REVIEW: This review briefly introduces the different murine models used in breast cancer research and proceeds to present the metabolomic studies reported so far to describe the deviant metabolic behavior associated to breast cancer, in each type of model: xenografts (cell- or patient-derived), spontaneous (naturally-occurring or genetically engineered) and carcinogen-induced. The type of sample and strategies followed are identified, as well as the main findings from of study. MAJOR CONCLUSIONS: Metabolomics has gradually become relevant in characterizing murine models of breast cancer, using either Nuclear Magnetic Resonance (NMR) or Mass Spectromety (MS). Both tissue and biofluids are matrixes of interest in this context, although in some type of models, reports have focused primarily on the former. The aims of tissue studies have comprised the search for mechanistic knowledge of carcinogenesis, metastasis development and response/resistance to therapies. Biofluid metabolomics has mainly aimed at finding non-invasive biomarkers for early breast cancer detection or prognosis determination. GENERAL SIGNIFICANCE: Metabolomics provides exquisite detail on murine tumor and systemic metabolism of breast cancer. This knowledge paves the way for the discovery of new biomarkers, potentially translatable to in vivo non-invasive patient follow-up.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Carcinogênese/metabolismo , Neoplasias Mamárias Experimentais/diagnóstico , Metabolômica/métodos , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mol Biol Rep ; 47(3): 1691-1702, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31970625

RESUMO

Phytotherapy has been used to treat a different type of diseases including cancer for a long time, and it was a source for different active anti-tumor agents. Oncolytic Newcastle disease virus (AMHA1) are very promising anti-tumor therapy. Nevertheless, NDV-based monotherapeutics have not been very useful to some resistant tumors. Thus, the efficiency of oncolytic NDV must enhance by combining NDV with other novel therapies. The current study aimed to determine the possibility of improving the oncolytic effect induced by NDV through Rheum ribes rhizomes extract administration in vitro and in vivo. Methods, the in vitro study include exposure of the crude extract of Rheum ribes alone or NDV alone or combination of both agents for 72 h. The cancer cells tested were murine mammary adenocarcinoma AMN3, Human Rhabdomyosarcoma RD, and Human Glioblastoma AMGM5, and using rat embryo fibroblast REF as normal control cells. MTT cell viability assay was used and analyzed for possible synergism using the Chou-Talalay analysis method. In vivo experiment included study the combination and the monotherapeutic modalities in the transplanted murine mammary adenocarcinoma AM3 line and tumor sections analyzed by histopathology. Results, Combination therapy of NDV-R. ribes showed enhanced oncolytic activity on cancer cells. With no cytotoxicity on normal cells. In vivo study showed that monotherapeutic modalities had lower growth inhibitory effect on transplanted tumors in mice in compare to combination therapy. Histopathological examination revealed the broader area of necrosis in tumors treated by combination therapy. In conclusion, the novel combination recommended for clinical application for cancer therapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias Mamárias Experimentais/terapia , Terapia Viral Oncolítica/métodos , Extratos Vegetais/farmacologia , Rheum/química , Rizoma/química , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada/métodos , Feminino , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Vírus da Doença de Newcastle/fisiologia , Vírus Oncolíticos/fisiologia , Ratos , Resultado do Tratamento
10.
J Immunol ; 204(4): 990-1000, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31900334

RESUMO

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1ß and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic Listeria monocytogenes-based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.


Assuntos
Vacinas Anticâncer/administração & dosagem , Neoplasias Pulmonares/terapia , Neoplasias Mamárias Experimentais/terapia , Células Supressoras Mieloides/imunologia , Neovascularização Patológica/terapia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada/métodos , Complemento C5a/imunologia , Complemento C5a/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Listeria monocytogenes/imunologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Células Supressoras Mieloides/metabolismo , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Neovascularização Patológica/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Microambiente Tumoral/imunologia
11.
Adv Mater ; 32(2): e1906711, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773830

RESUMO

Supramolecular nanomedicines, which use supramolecular design to improve the precision and effectiveness of pharmaceutical practice and optimize pharmacokinetic profiles, have gathered momentum to battle cancer and other incurable diseases, for which traditional small-molecular and macromolecular drugs are less effective. However, the lack of clinical approval of supramolecular assembly-based medicine underscores the challenges facing this field. A 2D nanodisc-based supramolecular structure is formed by a non-ionic heptamethine cyanine (Cy7) dye, which generates fluorescence self-quenching but unique photothermal and photoacoustic properties. These Cy7-based supramolecular nanodiscs exhibit passive tumor-targeting properties to not only visualize the tumor by near-infrared fluorescence imaging and photoacoustic tomography but also induce photothermal tumor ablation under irradiation. Due to the nature of organic small molecule, they induce undetectable acute toxicity in mice and can be eliminated by the liver without extrahepatic metabolism. These findings suggest that the self-assembling cyanine discs represent a new paradigm in drug delivery as single-component supramolecular nanomedicines that are self-delivering and self-formulating, and provide a platform technology for synergistic clinical cancer imaging and therapy.


Assuntos
Carbocianinas/química , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/terapia , Fototerapia/métodos , Nanomedicina Teranóstica/métodos , Animais , Feminino , Camundongos , Modelos Moleculares , Conformação Molecular
12.
Immunotherapy ; 11(18): 1555-1567, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31865872

RESUMO

Aim: Achievements in cancer immunotherapy require augmentation of a host's anti-tumor immune response for anti-cancer modality. Materials & methods: Different concentrations of recombinant anti-CD3 nanobody were administered at predetermined time intervals during a 24-day treatment period and then expression of angiogenic biomarkers including VEGFR2, MMP9 and CD31, as well as tumor cell proliferation marker ki67, was determined in tumor sections by immunohistochemistry. Furthermore, expression of cytokines was examined in peripheral blood of mice. Results: Based on our results, administration of nanobody could reduce biomarker expression in tumor sections. Tumor growth was also delayed and survival rate was increased in response to nanobody treatment. Moreover, expression of pro-inflammatory cytokines was reduced. Conclusion: In conclusion, we demonstrated that administration of nanobody could effectively suppress angiogenesis as well as tumor growth.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Complexo CD3/antagonistas & inibidores , Neoplasias Mamárias Experimentais/terapia , Anticorpos de Domínio Único/uso terapêutico , Indutores da Angiogênese/metabolismo , Inibidores da Angiogênese/imunologia , Animais , Antineoplásicos/imunologia , Citocinas/sangue , Feminino , Imunoterapia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Anticorpos de Domínio Único/imunologia , Taxa de Sobrevida , Carga Tumoral/efeitos dos fármacos
13.
Drug Deliv ; 26(1): 1254-1264, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760842

RESUMO

The therapeutic outcome of chemotherapy is limited, although it is still the preferent strategy for cancer therapy. By regulation of tumor microenvironment and introduction of another therapeutic manner for combination therapy can enhance the anticancer activity of chemotherapeutics. Herein, we have constructed a hybrid nanostructure which composed of manganese dioxide (MnO2) and doxorubicin (DOX) as well as IR780 by stabilizing with BSA (BMDI) in one-pot procedure to alleviate tumor hypoxia and enhance tumor growth inhibition. The MnO2 can react with H2O2 to generate oxygen, and additionally react with GSH to realize tumor microenvironment responsive drug controlled release. And the release Mn ions further enhanced the magnetic resonance signal which made the BMDI a promising contrast agent for MRI. Moreover, the introduction of MnO2 has enhanced the anticancer activity of DOX in vitro and in vivo, and efficiently suppressed the tumor growth. By further introducing with photothermal therapy (PTT), the tumor growth was almost inhibited. It demonstrated that the BMDI hybrid nanostructure has great potential in tumor growth inhibition as therapeutics carrier.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Hipertermia Induzida/métodos , Indóis/química , Neoplasias Mamárias Experimentais/terapia , Compostos de Manganês/química , Nanoestruturas/química , Óxidos/química , Fototerapia/métodos , Soroalbumina Bovina/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Células MCF-7 , Camundongos Nus , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
PLoS One ; 14(11): e0224309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31693710

RESUMO

In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Indometacina/administração & dosagem , Neoplasias Mamárias Experimentais/terapia , Mucina-1/imunologia , Animais , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Terapia Combinada/métodos , Feminino , Humanos , Imunogenicidade da Vacina/efeitos dos fármacos , Imunogenicidade da Vacina/imunologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Transgênicos , Mucina-1/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
15.
Aging (Albany NY) ; 11(22): 10711-10722, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754084

RESUMO

Previously, we reported that the administration of a p62/SQSTM1-encoding plasmid demonstrates high safety and signs of clinical benefits for human cancer patients. The treatment also suppressed tumor growth and metastasis in dogs and mouse models. Here we investigated some mechanistic aspects of these effects. In mammary tumors bearing-dogs, i.m. injections of p62 plasmid reduced tumor sizes and their aggressive potential in 5 out of 6 animals, with one carcinoma switching to adenoma. The treatment increased levels of smooth muscle actin in stroma cells and type III collagen in the extracellular matrix, which correlate with a good clinical prognosis. The p62 treatment also increased the abundance of intratumoral T-cells. Because of the role of adaptive immunity cannot be tested in dogs, we compared the protective effects of the p62 plasmid against B16 melanoma in wild type C57BL/6J mice versus their SCID counterpart lacking lymphocytes. The plasmid was only protective in the wild type strain. Also, p62 plasmid amplified the anti-tumor effect of T-cell transfer from tumor-bearing animals to animals challenged with the same tumors. We conclude that the plasmid acts via re-modeling of the tumor microenvironment, making it more favorable for increased anti-cancer immunity. Thus, the p62-encoding plasmid might be a new adjuvant for cancer treatments.


Assuntos
Terapia Genética/métodos , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Proteína Sequestossoma-1/genética , Microambiente Tumoral/imunologia , Animais , Cães , Feminino , Vetores Genéticos , Humanos , Neoplasias Mamárias Experimentais/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Plasmídeos
16.
Vaccine ; 37(49): 7256-7268, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31570181

RESUMO

Triple-negative breast cancer is a major health problem that lacks molecular targets for therapy. Neoepitopes represent a viable option to induce antitumor immune responses, but they have limitations, such as low immunogenicity and tolerance induction. Parvovirus B19 virus-like particles may be used to deliver neoepitopes to prime cellular immunity. We designed and evaluated the therapeutic effect of VP2 B19-virus-like particles, with multi-neoepitopes, in a 4T1 breast cancer model. Balb/c mice received four therapeutic immunizations with multi-neoepitopes-virus-like, wild type-virus-like, vehicle, or virus-like plus Cry1Ac adjuvant particles, intraperitoneally and peritumorally. Tumor growth, lung macro-metastasis, and specific immune responses were evaluated. Therapeutic administration of multi-epitopes virus-like particles significantly delayed tumor growth and decreased the lung macro-metastasis number, in comparison to treatment with wild type-virus-like particles, which surprisingly also elicited antitumoral effects that were improved with the adjuvant. Only treatments with multi-epitope virus-like particles induced specific proliferative responses of CD8 and CD4 T lymphocytes and Granzyme-B production in lymphatic nodes local to the tumor. Treatment with recombinant multiple neoepitopes-virus-like particles induced specific cellular responses, inhibited tumor growth and macro-metastasis, thus B19-virus-like particles may function as an effective delivery system for neoepitopes for personalized immunotherapy.


Assuntos
Epitopos/imunologia , Imunidade Celular/imunologia , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/terapia , Parvovirus B19 Humano/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Endotoxinas/imunologia , Feminino , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Proteínas Hemolisinas/imunologia , Imunização , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Parvovirus B19 Humano/genética
17.
Open Biol ; 9(10): 190061, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31594465

RESUMO

Blockade of inhibitory receptors (IRs) is one of the most effective immunotherapeutic approaches to treat cancer. Dysfunction of miRNAs is a major cause of aberrant expression of IRs and contributes to the immune escape of cancer cells. How miRNAs regulate immune checkpoint proteins in breast cancer remains largely unknown. In this study, downregulation of miRNAs was observed in PD-1-overexpressing CD8+ T cells using miRNA array analysis of mouse breast cancer homografts. The data reveal that miR-149-3p was predicted to bind the 3'UTRs of mRNAs encoding T-cell inhibitor receptors PD-1, TIM-3, BTLA and Foxp1. Treatment of CD8+ T cells with an miR-149-3p mimic reduced apoptosis, attenuated changes in mRNA markers of T-cell exhaustion and downregulated mRNAs encoding PD-1, TIM-3, BTLA and Foxp1. On the other hand, T-cell proliferation and secretion of effector cytokines indicative of increased T-cell activation (IL-2, TNF-α, IFN-γ) were upregulated after miR-149-3p mimic treatment. Moreover, the treatment with a miR-149-3p mimic promoted the capacity of CD8+ T cells to kill targeted 4T1 mouse breast tumour cells. Collectively, these data show that miR-149-3p can reverse CD8+ T-cell exhaustion and reveal it to be a potential antitumour immunotherapeutic agent in breast cancer.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Neoplasias Mamárias Experimentais/genética , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Citocinas/genética , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Imunoterapia/métodos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
18.
ACS Appl Mater Interfaces ; 11(46): 42904-42916, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657540

RESUMO

Potentiating systemic immunity against breast cancer is in the most urgent demand as breast cancer is less sensitive to immune checkpoint blockade. Although phototherapy and some chemotherapy can trigger immunogenic cell death (ICD) for T cell-mediated antitumor immune response, their immunotherapy efficacy is severely restricted by insufficient phototherapeutic capability and severe multidrug resistance (MDR). Inspired by both the hypersensitivity to phototherapy and the key role of MDR for mitochondria, a rationally engineered immunity amplifier via mitochondria-targeted photochemotherapeutic nanoparticles was, for the first time, achieved to fight against low-immunogenic breast cancer without additional immune agents. The newly synthesized task-specific mitochondria-targeted IR780 derivative (T780) was integrated with chemotherapeutic doxorubicin (DOX) to form multifunctional nanoparticles via an assembling strategy along with bovine serum albumin (BSA) as a biomimetic corona (BSA@T780/DOX NPs). The in situ enhancement in both phototherapy and MDR reversal by targeting mitochondria with BSA@T780/DOX NPs boosted highly efficient ICD toward excellent antitumor immune response. The newly developed strategy not only eradicated the primary tumor but also eliminated the bilateral tumors efficiently, as well as preventing metastasis and postsurgical recurrence, demonstrating great interest for fighting against low-immunogenic breast cancer.


Assuntos
Materiais Biomiméticos , Doxorrubicina , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Indóis , Neoplasias Mamárias Experimentais , Nanopartículas , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Bovinos , Linhagem Celular , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Indóis/química , Indóis/farmacologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Coroa de Proteína/química , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacologia
19.
ACS Appl Mater Interfaces ; 11(46): 43018-43030, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31660723

RESUMO

Traditional tumor treatments suffer from severe side effects on account of their invasive process and inefficient outcomes. Featuring a unique physical microenvironment, the tumor microenvironment (TME) provides a new research direction for designing more efficient and safer treatment paradigms. In this study, we fabricated a polydopamine (PDA)-based TME-responsive nanosystem, which successfully integrates glucose degradation, the Fenton reaction, and photothermal therapy for efficient cancer therapy. Through a convenient hydrothermal method, Fe2+-doped Fe(II)-PDA nanoparticles were successfully fabricated, which show an excellent photothermal effect and interesting reactivity for the Fenton reaction. Instead of introducing toxic anticancer agents, natural glucose oxidase (GOD) was grafted on Fe(II)-PDA, forming a cascade catalytic nanomedicine for a specific response to the glucose in TME. GOD grafted on Fe(II)-PDA-GOD is ought to catalyze abundant glucose in TME into gluconic acid and H2O2. The concomitant generation of H2O2 can enhance the efficiency of the sequential Fenton reaction, producing abundant hydroxyl radicals (•OH) for cancer therapy. Besides, the overconsumption of intratumoral glucose also could inhibit tumor growth by reducing the energy supply. Taken together, the in vitro and in vivo antitumor studies of such TME-based Fe(II)-PDA-GOD nanosystems displayed a favorable synergistic potency of glucose degradation, the Fenton reaction, and photothermal therapy against tumor growth. Our design expands the biological application of multifunctional PDA while providing novel strategies toward effective antitumor treatment with minimal side effects.


Assuntos
Compostos Ferrosos , Hipertermia Induzida , Indóis , Neoplasias Mamárias Experimentais , Nanopartículas , Fototerapia , Polímeros , Microambiente Tumoral/efeitos dos fármacos , Animais , Catálise , Linhagem Celular Tumoral , Feminino , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Indóis/química , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros/química , Polímeros/farmacologia
20.
ACS Appl Mater Interfaces ; 11(46): 42932-42942, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31588738

RESUMO

Radiotherapy and chemotherapy are both common clinical treatment methods. The combination of the two treatments can decrease tumor recurrence. In this study, bismuth-based mesoporous litchi-shaped Na0.2Bi0.8O0.35F1.91:20%Yb (NBOF) nanoparticles (NPs) have been reported as a radiosensitizer and as a nanovehicle for loading and slow-releasing doxorubicin (DOX). After assembling with amphiphilic poly(ethylene glycol) (PEG), NBOF-DOX-PEG qualified with excellent aqueous dispersibility and the enhanced tumor radiation and chemo-synergistic therapy characteristics. The formation of NBOF revealed the oxygen element in NBOF came from H2O and air in the synthesis and post-treatment process, and the size of NBOF could be adjusted by changing the concentration of doped Yb ion. The average size of NBOF was ca. 80 nm. Brunauer-Emmett-Teller results demonstrated the mesoporous structure of NBOF. So DOX could be loaded in NBOF and the optimized loading content was 39%. Then, NBOF-PEG exhibited a strong computed tomography signal whitening ability and enhanced radiotherapy effect. Combined with the chemotherapy ability of DOX, NBOF-DOX-PEG NPs presented remarkable synergistic tumor elimination ability. Meanwhile, NBOF-DOX-PEG NPs qualified for excellent biosafety. Our study not only proved the combined chemo- and radiotherapy for enhancing therapeutic effect but also supplied a functional Bi-based mesoporous nanovehicle for constructing an intelligent theranostic platform.


Assuntos
Bismuto , Quimiorradioterapia , Doxorrubicina , Portadores de Fármacos , Neoplasias Mamárias Experimentais , Nanoestruturas , Radiossensibilizantes , Tomografia Computadorizada por Raios X , Animais , Bismuto/química , Bismuto/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Porosidade , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia
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