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1.
Res Vet Sci ; 138: 116-124, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34129994

RESUMO

Availability of graft materials to fill up osseous defects has always been a concern in orthopaedic surgeries. Deer antler material is a primary bone structure that is easy to collect and could serve as a xenograft. This study examines the behaviour of red deer antler trabecular cylinders in critical size distal femoral epiphyseal defects in 11 rabbits, and evaluates the effect of the decellularization protocols. Two preparation regimes (A and B) were used, with and without lipids and proteins. Radiographs were taken immediately after surgery and after euthanasia 12 weeks post-implantation. Histological evaluation was performed on non-decalcified 10-µm sections with a van Gieson picro-fuchsin staining protocol. A region of interest was defined for each histological section, evaluating the inflammatory reaction, the fibrosis process, and the osteogenesis. Each histological section was microradiographed to evaluate bone contact, presence of synostosis, remodelling and ossification processes. All antler cylinders were successfully implanted. Final radiographic analysis demonstrated osteointegration of most implants at various stages. Light to moderate inflammation around the grafts was noted with only one case showing full encapsulation. A variable degree of intimacy between implant and host bone was evidenced, with bone remodelling and osteogenesis of various intensity being present in all implanted sites. No differences were found between group A and B. Removal of lipids and proteins in the grafts surprisingly did not seem to matter. Decellularization and sterilization protocols may be advocated. Although it presents several limitations, this study shows some promising results regarding antler trabecular bone osteointegration.


Assuntos
Chifres de Veado/química , Remodelação Óssea , Osso Esponjoso/transplante , Cervos , Osteogênese , Coelhos/cirurgia , Transplante Heterólogo/instrumentação , Animais , Masculino , Modelos Animais
2.
Nat Commun ; 12(1): 3840, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158498

RESUMO

Histopathological level imaging in a non-invasive manner is important for clinical diagnosis, which has been a tremendous challenge for current imaging modalities. Recent development of ultra-high-field (UHF) magnetic resonance imaging (MRI) represents a large step toward this goal. Nevertheless, there is a lack of proper contrast agents that can provide superior imaging sensitivity at UHF for disease detection, because conventional contrast agents generally induce T2 decaying effects that are too strong and thus limit the imaging performance. Herein, by rationally engineering the size, spin alignment, and magnetic moment of the nanoparticles, we develop an UHF MRI-tailored ultra-sensitive antiferromagnetic nanoparticle probe (AFNP), which possesses exceptionally small magnetisation to minimize T2 decaying effect. Under the applied magnetic field of 9 T with mice dedicated hardware, the nanoprobe exhibits the ultralow r2/r1 value (~1.93), enabling the sensitive detection of microscopic primary tumours (<0.60 mm) and micrometastases (down to 0.20 mm) in mice. The sensitivity and accuracy of AFNP-enhanced UHF MRI are comparable to those of the histopathological examination, enabling the development of non-invasive visualization of previously undetectable biological entities critical to medical diagnosis and therapy.


Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Magnetismo , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Neoplasias/patologia , Células RAW 264.7 , Ratos Wistar , Transplante Heterólogo
3.
J Med Chem ; 64(11): 7404-7421, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34038111

RESUMO

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.


Assuntos
Compostos Policíclicos/química , Proteínas de Ligação a RNA/metabolismo , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/metabolismo , Enoxacino/química , Enoxacino/metabolismo , Enoxacino/farmacologia , Enoxacino/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Compostos Policíclicos/metabolismo , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Ribonuclease III/química , Ribonuclease III/metabolismo , Relação Estrutura-Atividade , Transcriptoma/efeitos dos fármacos , Transplante Heterólogo
4.
J Med Chem ; 64(11): 7261-7271, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043360

RESUMO

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.


Assuntos
Antineoplásicos/química , Azetidinas/química , Antígeno CD47/metabolismo , Nitrocompostos/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Antígeno CD47/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Meia-Vida , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Nitrocompostos/farmacologia , Nitrocompostos/uso terapêutico , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-myc/genética , Relação Estrutura-Atividade , Transplante Heterólogo , Macrófagos Associados a Tumor/citologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo
5.
J Med Chem ; 64(11): 7735-7745, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34047189

RESUMO

Owing to the complex anatomical structure, precise resection of a tumor while maintaining adjacent tissue is a challenge in radical prostatectomy for prostate cancer (PCa). Optical imaging in near-infrared window II (NIR-II) is a promising technology for intraoperative guidance, whereas there is no available probe for PCa yet. In this article, a novel probe (PSMA-1092) bearing two prostate-specific membrane antigen (PSMA) binding motifs was developed, displaying excellent optical properties (λmax = 1092 nm) and ultrahigh affinity (Ki = 80 pM) toward PSMA. The tumor was visualized with high resolution (tissue-to-normal tissue ratio = 7.62 ± 1.05) and clear margin by NIR-II imaging using PSMA-1092 in a mouse model. During the tumor resection, residual tumors missed by visible inspection were detected by the real-time imaging. Overall, PSMA-1092 displayed excellent performance in delineating the tumor margin and detecting residual tumors, demonstrating promising potential for precise PCa tumor resection in clinical practice.


Assuntos
Corantes Fluorescentes/química , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Estabilidade de Medicamentos , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Nus , Antígeno Prostático Específico/química , Prostatectomia , Neoplasias da Próstata/cirurgia , Espectroscopia de Luz Próxima ao Infravermelho , Transplante Heterólogo
6.
Cancer Sci ; 112(7): 2592-2606, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33938090

RESUMO

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.


Assuntos
Modelos Animais de Doenças , Imunoterapia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/uso terapêutico , Citocinas/metabolismo , Desenvolvimento de Medicamentos , Engenharia Genética , Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoterapia Adotiva/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células Matadoras Naturais/imunologia , Camundongos , Camundongos SCID , Neoplasias/imunologia , Medicina de Precisão , Pesquisa Médica Translacional , Transplante Heterólogo
7.
Pediatr Surg Int ; 37(8): 1031-1040, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34031745

RESUMO

OBJECTIVE: The lack of appropriate preclinical models of ovarian yolk sac tumor (OYST) is currently hindering the pursuit of new methods of treatment and investigation of the pathogenesis of the disease. We developed and characterized an OYST patient-derived xenograft (PDX) model in this study. METHODS: Tumor fragments from a patient with an OYST were implanted subcutaneously into BALB/c Nude mice. Engrafted xenografts were compared with the original tumor according to histology, immunohistochemistry, humanized identified, and drug efficacy testing with in vivo treatment programs. RESULTS: There was a high degree of histologic and immunohistochemical (IHC) resemblance between the established PDX model and its corresponding human tumors. Bleomycin, etoposide, and cisplatin (JEB) chemotherapy regimens were effective in clinical patients and were effective in the OYST PDX model; therefore, the effect of PDX intervention was consistent with clinical outcomes of OYSTs. CONCLUSION: We have successfully established an OYST PDX model. This OYST model preserves the basic molecular features of the primary human tumor, thereby providing a valuable method to preclinically evaluate new treatments and explore disease pathogenesis.


Assuntos
Tumor do Seio Endodérmico/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/patologia , Transplante Heterólogo/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antineoplásicos/uso terapêutico , Bleomicina/uso terapêutico , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Tumor do Seio Endodérmico/tratamento farmacológico , Tumor do Seio Endodérmico/genética , Etoposídeo/uso terapêutico , Feminino , Xenoenxertos/transplante , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética
8.
Nat Commun ; 12(1): 3142, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035264

RESUMO

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Cardiomiopatias/tratamento farmacológico , Macrófagos/imunologia , Pré-Albumina/antagonistas & inibidores , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Cardiomiopatias/patologia , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Mutação , Miocárdio/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Pré-Albumina/genética , Pré-Albumina/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/imunologia , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Heterólogo
9.
J Med Chem ; 64(10): 6902-6923, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34000802

RESUMO

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.


Assuntos
Proteínas de Membrana/agonistas , Nucleotídeos Cíclicos/química , Pirimidinas/química , Administração Intravenosa , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Meia-Vida , Humanos , Imunoterapia , Proteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/patologia , Neoplasias/terapia , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/uso terapêutico , Fosfatos/química , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo
10.
J Med Chem ; 64(10): 6949-6971, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34006099

RESUMO

Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγ EC50 = 0.245 µM and HDAC4 IC50 = 1.1 µM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 µM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.


Assuntos
Desenho de Fármacos , Histona Desacetilases/metabolismo , PPAR gama/metabolismo , Proteínas Repressoras/metabolismo , Tiazolidinedionas/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , PPAR gama/química , PPAR gama/genética , Proteínas Repressoras/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Ativação Transcricional/efeitos dos fármacos , Transplante Heterólogo
11.
J Med Chem ; 64(10): 6985-6995, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33942608

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Administração Oral , Animais , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirróis/metabolismo , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Transplante Heterólogo
12.
J Med Chem ; 64(10): 6720-6729, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33961424

RESUMO

As c-MYC is one of the central players in triple-negative breast cancer (TNBC) oncogenesis, inhibiting c-MYC expression would be an effective anticancer strategy. Transcription-induced negative supercoiling is crucial in the regulation of c-MYC transcription, which facilitates the formation of a G4 structure in NHE III1 that can silence the transcription. However, topoisomerase 1 (Topo1) can dissipate this negative supercoiling, leading to continuous activation of c-MYC transcription. Thus, dual ligands targeting both Topo1 and c-MYC G4 appear to be significant in cancer therapy. In this study, a series of new dibenzoquinoxaline derivatives were designed, synthesized, and evaluated for both Topo1 and c-MYC inhibition. Among them, 5 was identified as the most promising dual ligand, which could effectively inhibit Topo1 activity and strongly stabilize c-MYC G4, thereby inhibiting cancer cell growth. Accordingly, this work suggests that this dual-targeting strategy may be effective in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/química , Quadruplex G/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Quinoxalinas/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Feminino , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinoxalinas/farmacologia , Quinoxalinas/uso terapêutico , Transplante Heterólogo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
13.
J Med Chem ; 64(10): 6877-6901, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33999621

RESUMO

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.


Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tiazóis/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Meia-Vida , Humanos , Imidazóis/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Tiazóis/metabolismo , Transplante Heterólogo
14.
BMC Med Ethics ; 22(1): 37, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794874

RESUMO

BACKGROUND: The transplantation of porcine islet cells provides a new potential therapy to treat patients with type 1 diabetes mellitus (T1DM). Compared to other biomedical technologies, xenotransplantation stands out in terms of its involvement of animals as graft sources, as well as the possible transmission of infectious diseases. As these aspects are especially relevant for potential xenotransplantation recipients, it is important to assess their opinion regarding this technology, in particular in terms of the requirements that should be met in the informed consent process for xenotransplantation. METHODS: We conducted qualitative interviews with seven T1DM patients to assess their information needs prior to xenotransplantation. Before the interview, the participants received a model informed consent form for a clinical trial with porcine islet cells transplantation. The interviews were transcribed and analysed using qualitative content analysis. RESULTS: In the interviews, we identified several requirements that are crucial for patients with T1DM in order to consider xenotransplantation as a potential treatment option: therapy-related requirements, professional care and supervision, successful behaviour and attitude management, improving quality of life, and managing control/self-determination challenges. Regarding the informed consent form, several of the participants' questions remained open and should be addressed in more detail. The interviewees stressed the importance of personal consultations. CONCLUSIONS: To become a sustainable therapeutic option, patients especially expected an improved diabetes control and a reduction of diabetes-related burdens. Health-related aspects prove to be pivotal for diabetic patients when considering porcine islet cell transplantation. The use of pigs as source for organ retrievals was not considered as problematic.


Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Consentimento Livre e Esclarecido , Transplante das Ilhotas Pancreáticas/métodos , Transplante Heterólogo/ética , Animais , Diabetes Mellitus Tipo 1/psicologia , Humanos , Transplante das Ilhotas Pancreáticas/ética , Seleção de Pacientes , Qualidade de Vida , Suínos
15.
J Med Chem ; 64(8): 4787-4809, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822622

RESUMO

To investigate the importance of the chirality and precise structure at position 3(1') of pyropheophorbide-a for tumor cell specificity and photodynamic therapy (PDT), a series of photosensitizers (PSs) was synthesized: (a) with and without chirality at position 3(1'), (b) alkyl ether chain with a variable number of chiral centers, (c) hexyl ether versus thioether side chain, and (d) methyl ester versus carboxylic acid group at position 172. The cellular uptake and specificity were defined in human lung and head/neck cancer cells. PSs without a chiral center and with an alkyl chain or thioether functionalities showed limited uptake and PDT efficacy. Replacing the methyl group at the chiral center with a propyl group or introducing an additional chiral center improved cellular retention and tumor cell specificity. Replacing the carboxylic acid with methyl ester at position 172 lowered cellular uptake and PDT efficacy. A direct correlation between the PS uptake in vitro and in vivo was identified.


Assuntos
Clorofila/análogos & derivados , Fármacos Fotossensibilizantes/metabolismo , Animais , Clorofila/química , Clorofila/metabolismo , Clorofila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Luz , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Solubilidade , Estereoisomerismo , Transplante Heterólogo , Células Tumorais Cultivadas
16.
J Med Chem ; 64(8): 4841-4856, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33826325

RESUMO

Proteins adopt unique folded secondary and tertiary structures that are responsible for their remarkable biological properties. This structural complexity is key in designing efficacious peptides that can mimic the three-dimensional structure needed for biological function. In this study, we employ different chemical strategies to induce and stabilize a ß-hairpin fold of peptides targeting cholecystokinin-2 receptors for theranostic application (combination of a targeted therapeutic and a diagnostic companion). The newly developed peptides exhibited enhanced folding capacity as demonstrated by circular dichroism (CD) spectroscopy, ion-mobility spectrometry-mass spectrometry, and two-dimensional (2D) NMR experiments. Enhanced folding characteristics of the peptides led to increased biological potency, affording four optimal Ga-68 labeled radiotracers ([68Ga]Ga-4b, [68Ga]Ga-11b-13b) targeting CCK-2R. In particular, [68Ga]Ga-12b and [68Ga]Ga-13b presented improved metabolic stability, enhanced cell internalization, and up to 6 fold increase in tumor uptake. These peptides hold great promise as next-generation theranostic radiopharmaceuticals.


Assuntos
Neoplasias/diagnóstico , Peptídeos/química , Compostos Radiofarmacêuticos/química , Receptor de Colecistocinina B/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Radioisótopos de Gálio/química , Humanos , Camundongos , Camundongos Nus , Neoplasias/patologia , Peptídeos/síntese química , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Medicina de Precisão , Ligação Proteica , Estrutura Terciária de Proteína , Compostos Radiofarmacêuticos/metabolismo , Receptor de Colecistocinina B/química , Distribuição Tecidual , Transplante Heterólogo
17.
J Med Chem ; 64(8): 4532-4552, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822606

RESUMO

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.


Assuntos
Antígenos de Superfície/metabolismo , Antineoplásicos/metabolismo , Corantes Fluorescentes/química , Glutamato Carboxipeptidase II/metabolismo , Ligantes , Animais , Antígenos de Superfície/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glutamato Carboxipeptidase II/química , Humanos , Masculino , Camundongos , Camundongos Nus , Imagem Óptica , Neoplasias da Próstata/tratamento farmacológico , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante Heterólogo
18.
J Med Chem ; 64(9): 5485-5499, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33861929

RESUMO

Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate-copper complexes, {[CuII(L)(Cl)] 1, [CuII2(L)2(NO3)2] 2, and [CuII2CuI(L)2(Br)3] 3}, to assess their antipancreatic cancer activities. Complexes 1-3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC50 than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells' growth in a mouse xenograft model.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Cobre/química , Hidrazinas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Ferroptose/efeitos dos fármacos , Meia-Vida , Humanos , Hidrazinas/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Mitocôndrias/química , Mitocôndrias/metabolismo , Conformação Molecular , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Transplante Heterólogo
19.
J Med Chem ; 64(9): 5593-5602, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33901402

RESUMO

Tumor hypoxia is a major factor responsible for tumor progression, metastasis, invasion, and treatment resistance, leading to low local tumor control and recurrence after radiotherapy in cancers. Here,18F-positron emission tomography (PET) probes are developed for visualizing viable hypoxic cells in biopsies. Pimonidazole derivatives and nitroimidazole-based agents bearing sulfonyl linkers were evaluated. A small-animal PET study showed that the tumor uptake of [18F]-23 [poly(ethylene glycols) (PEG)-sulfonyl linker] of 3.36 ± 0.29%ID/g was significantly higher (P < 0.01) than that of [18F]-20 (piperazine-linker tracer, 2.55 ± 0.49%ID/g) at 2 h postinjection in UPPL tumors. The tumor-to-muscle uptake ratio of [18F]-23 (2.46 ± 0.48 at 2 h pi) was well improved compared with that of [18F]-FMISO (1.25 ± 0.14 at 2 h pi). A comparable distribution pattern was observed between ex vivo autoradiography of [18F]-23 and pimonidazole staining of the neighboring slice, indicating that [18F]-23 is a promising PET agent for hypoxia imaging.


Assuntos
Neoplasias/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Hipóxia Tumoral , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Nitroimidazóis/química , Polietilenoglicóis/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Ácidos Sulfínicos/química , Transplante Heterólogo
20.
J Med Chem ; 64(10): 6814-6826, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33900758

RESUMO

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Metionina Adenosiltransferase/antagonistas & inibidores , Sítio Alostérico , Animais , Proliferação de Células , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Técnicas de Inativação de Genes , Células HCT116 , Meia-Vida , Humanos , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos , S-Adenosilmetionina/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo
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