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1.
Int J Nanomedicine ; 15: 5459-5471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801700

RESUMO

Purpose: Indocyanine green (ICG), a near infrared (NIR) dye clinically approved in medical diagnostics, possesses great heat conversion efficiency, which renders itself as an effective photosensitizer for photothermal therapy (PTT) of cancer. However, there remain bottleneck challenges for use in PTT, which are the poor photo and plasma stability of ICG. To address these problems, in this research, ICG-loaded silver nanoparticles were prepared and evaluated for the applicability as an effective agent for photothermal cancer therapy. Methods and Results: PEGylated bovine serum albumin (BSA)-coated silver core/shell nanoparticles were synthesized with a high loading of ICG ("PEG-BSA-AgNP/ICG"). Physical characterization was carried out using size analyzer, transmission electron microscopy, and Fourier transform infrared spectrophotometry to identify successful preparation and size stability. ICG-loading content and the photothermal conversion efficiency of the particles were confirmed with inductively coupled plasma mass spectrometry and laser instruments. In vitro studies showed that the PEG-BSA-AgNP/ICG could provide great photostability for ICG, and their applicability for PTT was verified from the cellular study results. Furthermore, when the PEG-BSA-AgNP/ICG were tested in vivo, study results exhibited that ICG could stably remain in the blood circulation for a markedly long period (plasma half-life: 112 min), and about 1.7% ID/g tissue could be accumulated in the tumor tissue at 4 h post-injection. Such nanoparticle accumulation in the tumor enabled tumor surface temperature to be risen to 50°C (required for photo-ablation) by laser irradiation and led to successful inhibition of tumor growth in the B16F10 s.c. syngeneic nude mice model, with minimal systemic toxicity. Conclusion: Our findings demonstrated that PEG-BSA-AgNPs could serve as effective carriers for delivering ICG to the tumor tissue with great stability and safety.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas Metálicas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Difusão Dinâmica da Luz , Meia-Vida , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Melanoma Experimental/tratamento farmacológico , Camundongos Endogâmicos ICR , Camundongos Nus , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química , Soroalbumina Bovina/química , Prata/química , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Int J Nanomedicine ; 15: 5279-5288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801691

RESUMO

Introduction: Today, a new paradigm has emerged for cancer treatment introducing combination therapies. Doxil, a liposomal doxorubicin serving as a chemotherapeutic agent, is an effective immunogenic killer of cancer cells. Anti-CTLA-4 has been approved for the treatment of some cancers, including melanoma, but side effects have limited its therapeutic potential. Methods: In this study, two approaches were utilized to increase treatment efficiency and decrease the side effects of anti-CTLA-4, combining it with chemotherapy and encapsulation in a PEGylated liposome. A different sequence of anti-CTLA-4 and Doxil was assessed in combination therapy using non-liposomal and liposomal anti-CTLA-4. Results: Our results showed that liposomal anti-CTLA-4 reduced the size of established tumors and increased survival in comparison with non-liposomal anti-CTLA-4 in a well-established B16 mouse melanoma model. In combination therapy with Doxil, only the administration of anti-CTLA-4 before Doxil showed synergism in both non-liposomal and liposomal form and increased the CD8+/regulatory T cell ratio. Discussion: In summary, our results demonstrate the potential of utilizing a nanocarrier system for the delivery of checkpoint blockers, such as anti-CTLA-4 which further showed potential in a combination therapy, especially when administered before chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CTLA-4/imunologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Lipossomos/química , Camundongos Endogâmicos C57BL , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Linfócitos T Reguladores/efeitos dos fármacos
3.
Mol Biol (Mosk) ; 54(2): 267-277, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392196

RESUMO

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Dacarbazina/farmacologia , Melanoma Experimental/tratamento farmacológico , RNA/farmacologia , Animais , Imunoterapia , Fígado/efeitos dos fármacos , Camundongos , Baço/imunologia
4.
PLoS One ; 15(5): e0233789, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470095

RESUMO

BACKGROUND: With more than 18 million annual new cases, cancer belongs to the major challenges of modern healthcare. Surgical resection of solid tumours under general anaesthesia is the prime therapy. Different aspects of anaesthesia are under discussion to independently influence the long-term outcome of cancer patients. Most recently, the commonly used volatile anaesthetics like sevoflurane have entered the spotlight, as retrospective studies suggest a detrimental outcome in certain cancer aetiologies with sparse mechanistic understanding. Our objective was to investigate this concept in a murine melanoma model, herein comparing the consequence of inhalative and injection anesthesia on tumour composition and growth. METHODS: We used a murine model of malignant melanoma in male, adult C57BL/6 mice (n = 92), induced by the subcutaneous injection of B16-F10 cells. We either exposed the melanoma cells to sevoflurane before implantation or subjected the animals to single or double anaesthesia with either volatile or injection drugs. After a maximum follow-up of 4 weeks, leucocytes within the tumour microenvironment (TME) were comprehensively analysed by flow cytometry with focus on tumor-associated macrophages (TAM). RESULTS: We found that exposure of melanoma cells to sevoflurane before implantation induced long-lasting transcriptome changes and aggravated tumour growth, without extensive changes of the TME. Contrastingly, both a single and double anaesthesia with sevoflurane led to a significant reduction of TAMs (injection vs. sevoflurane: 2,0 vs. 0.3% and 1.2 vs. 0.6%, respectively), whilst increasing PD-L1 expression on the remaining cells (mean fluorescent intensity injection vs. sevoflurane: 3,804 vs. 7,143 and 9,090 vs. 32,228, respectively). No changes in tumour growth were observed in these groups. CONCLUSION: In sharp contrast to the detrimental impact of sevoflurane on patients' outcome reported in retrospective clinical studies, we propose here that sevoflurane might actually exert a beneficial effect by decreasing TAMs within the TME, rendering the tumour again susceptible for cytotoxic T cells and immunotherapies. Further research is warranted to delineate, how these results translate into the clinic.


Assuntos
Macrófagos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Melanoma/tratamento farmacológico , Sevoflurano/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Life Sci ; 256: 117702, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32387411

RESUMO

There is a rapid increase in the incidence of melanoma which has led to a global crisis. Thus, there is a great need for developing novel, safe and effective drugs for the treatment of melanoma. Hispolon is a small molecular weight polyphenol derived from Phellinus linteus, which has antioxidant, anti-inflammatory and anti-proliferative activities. Hispolon has been reported to induce apoptosis in gastric cancer, hepatocellular carcinoma, and myeloid leukemia. However, the anticancer effect in melanoma is not well elucidated. Thus, our present study was to investigate the anti-cancer effect of hispolon on melanoma cancer cells. B16BL6 cells were treated with different concentrations of hispolon for 24 h and the effect on oxidative stress, mitochondrial functions, apoptosis and cell proliferation were studied. Hispolon is a potent generator of reactive oxygen species, nitrite and lipid peroxide levels. Furthermore, it significantly inhibits the expression of Bcl-2 and promotes the expression of Bax, increases the activity of caspase 1 and 3, inhibits mitochondrial Complex I and IV activities. By the above mechanisms, hispolon dose-dependently exhibited the antimelanoma effect similar to the well established pharmacological agent, curcumin. Thus, hispolon can be a potent anti-melanoma drug in the future if the pharmacodynamic effects and the toxicological studies are appropriately carried out.


Assuntos
Antineoplásicos/farmacologia , Catecóis/farmacologia , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Catecóis/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Melanoma Experimental/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/patologia
6.
Cancer Immunol Immunother ; 69(10): 1959-1972, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32388678

RESUMO

Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic-polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™-mPAP-Poly I:C-Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA).


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Colesterol/administração & dosagem , Melanoma Experimental/imunologia , Fosfolipídeos/administração & dosagem , Neoplasias da Próstata/imunologia , Saponinas/administração & dosagem , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Interferon gama/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Poli I-C/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Exp Pathol ; 101(3-4): 106-121, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32452573

RESUMO

Plant biodiversity is a source of potential natural products for the treatment of many diseases. One of the ways of discovering new drugs is through the cytotoxic screening of extract libraries. The present study evaluated 196 extracts prepared by maceration of Brazilian Atlantic Forest trees with organic solvents and distilled water for cytotoxic and antimetastatic activity. The MTT assay was used to screen the extract activity in MCF-7, HepG2 and B16F10 cancer cells. The highest cytotoxic extract had antimetastatic activity, as determined in in vitro assays and melanoma murine model. The organic extract of the leaves of Athenaea velutina (EAv) significantly inhibited migration, adhesion, invasion and cell colony formation in B16F10 cells. The phenolic compounds and flavonoids in EAv were identified for the first time, using flow injection with electrospray negative ionization-ion trap tandem mass spectrometry analysis (FIA-ESI-IT-MSn ). EAv markedly suppressed the development of pulmonary melanomas following the intravenous injection of melanoma cells to C57BL/6 mice. Stereological analysis of the spleen cross-sections showed enlargement of the red pulp area after EAv treatment, which indicated the activation of the haematopoietic system. The treatment of melanoma-bearing mice with EAv did not result in liver damage. In conclusion, these findings suggest that A velutina is a source of natural products with potent antimetastatic activity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Florestas , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Melanoma Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Solanaceae/química , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Células MCF-7 , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Metástase Neoplásica , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química
8.
J Cancer Res Clin Oncol ; 146(6): 1489-1499, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32246216

RESUMO

PURPOSE: To investigate the synergistic effect of resveratrol on the bystander effect of TK/GCV suicide gene system in melanoma cells. METHODS: The effect of resveratrol on the growth of B16 cells and the synergistic effect of resveratrol with or without GCV were detected by MTT assay and high content screening assay. The effect of resveratrol on GJIC function was detected by flow cytometry combined with fluorescence tracer and fluorescence microscope, and the expression of gap junction protein was detected by western blotting. Synergistic killing effect of resveratrol plus TK/GCV was tested in vivo using transplanted melanoma model. RESULTS: In vitro, resveratrol can enhanced GJ function and upregulated Cx32 and Cx43 protein expression in B16 cells. Resveratrol synergized with GCV to kill mixed B16 melanoma cells (20% TK+ cells and 80% TK- cells) and to improve apoptosis rate of TK- cells (the bystander effect of TK system), and the synergistic action was reversed by the GJ inhibitor AGA. In vivo, when B16 cells were mixed with 30% TK+ B16 cells, significantly reduced tumor weight and volume were observed after combinational treatment with resveratrol plus GCV as compared with GCV or resveratrol treatment alone. CONCLUSIONS: Resveratrol could synergistically enhance the killing effect of TK/GCV suicide gene system in melanoma B16 cells and transplanted melanoma. It might be a promising adjuvant of TK/GCV therapy.


Assuntos
Ganciclovir/uso terapêutico , Terapia Genética , Melanoma Experimental/terapia , Resveratrol/uso terapêutico , Timidina Quinase/genética , Animais , Efeito Espectador , Linhagem Celular Tumoral , Sinergismo Farmacológico , Genes Transgênicos Suicidas , Melanoma Experimental/tratamento farmacológico , Camundongos
9.
Int J Nanomedicine ; 15: 1915-1928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256068

RESUMO

Background: Melanoma is the most common symptom of aggressive skin cancer, and it has become a serious health concern worldwide in recent years. The metastasis rate of malignant melanoma remains high, and it is highly difficult to cure with the currently available treatment options. Effective yet safe therapeutic options are still lacking. Alternative treatment options are in great demand to improve the therapeutic outcome against advanced melanoma. This study aimed to develop albumin nanoparticles (ANPs) coated with macrophage plasma membranes (RANPs) loaded with paclitaxel (PTX) to achieve targeted therapy against malignant melanoma. Methods: Membrane derivations were achieved by using a combination of hypotonic lysis, mechanical membrane fragmentation, and differential centrifugation to empty the harvested cells of their intracellular contents. The collected membrane was then physically extruded through a 400 nm porous polycarbonate membrane to form macrophage cell membrane vesicles. Albumin nanoparticles were prepared through a well-studied nanoprecipitation process. At last, the two components were then coextruded through a 200 nm porous polycarbonate membrane. Results: Using paclitaxel as the model drug, PTX-loaded RANPs displayed significantly enhanced cytotoxicity and apoptosis rates compared to albumin nanoparticles without membrane coating in the murine melanoma cell line B16F10. RANPs also exhibited significantly higher internalization efficiency in B16F10 cells than albumin nanoparticles without a membrane coating. Next, a B16F10 tumor xenograft mouse model was established to explore the biodistribution profiles of RANPs, which showed prolonged blood circulation and selective accumulation at the tumor site. PTX-loaded RANPs also demonstrated greatly improved antitumor efficacy in B16F10 tumor-bearing mouse xenografts. Conclusion: Albumin-based nanoscale delivery systems coated with macrophage plasma membranes offer a highly promising approach to achieve tumor-targeted therapy following systemic administration.


Assuntos
Albuminas/química , Macrófagos/citologia , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/química , Feminino , Humanos , Macrófagos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Paclitaxel/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
10.
PLoS One ; 15(3): e0228339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214351

RESUMO

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/- (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon gama/metabolismo , Masculino , Melanoma Experimental/patologia , Camundongos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico
11.
Proc Natl Acad Sci U S A ; 117(14): 8001-8012, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32193336

RESUMO

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Melanoma Experimental/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Feminino , Dosagem de Genes , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/mortalidade , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/genética , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Prognóstico , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Nanomedicine ; 15: 137-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021170

RESUMO

Purpose: Traditional chemotherapy is accompanied by significant side effects, which, in many aspects, limits its treatment efficacy and clinical applications. Herein, we report an oxidative responsive polymersome nanosystem mediated by near infrared (NIR) light which exhibited the combination effect of photodynamic therapy (PDT) and chemotherapy. Methods: In our study, poly (propylene sulfide)20-bl-poly (ethylene glycol)12 (PPS20-b-PEG12) block copolymer was synthesized and employed to prepare the polymersome. The hydrophobic photosensitizer zinc phthalocyanine (ZnPc) was loaded in the shell and the hydrophilic doxorubicin hydrochloride (DOX·HCl) in the inner aqueous space of the polymersome. Results: Under the irradiation of 660 nm NIR light, singlet oxygen 1O2 molecules were generated from ZnPc to oxidize the neighbouring sulfur atoms on the PPS block which eventually ruptured the intact structure of polymersomes, leading to the release of encapsulated DOX·HCl. The released DOX and the 1O2 could achieve a combination effect for cancer therapy if the laser activation and drug release occur at the tumoral sites. In vitro studies confirmed the generation of singlet oxygen and DOX release by NIR irradiation. In vivo studies showed that such a combined PDT-chemotherapy nanosystem could accumulate in A375 tumors efficiently, thus leading to significant inhibition on tumor growth as compared to PDT (PZ group) or chemotherapy alone (DOX group). Conclusion: In summary, this oxidation-sensitive nanosystem showed excellent anti-tumor effects by synergistic chemophotodynamic therapy, indicating that this novel drug delivery strategy could potentially provide a new means for cancer treatments in clinic.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Melanoma Experimental/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Humanos , Indóis/administração & dosagem , Indóis/química , Lasers , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Polímeros/química , Oxigênio Singlete/farmacocinética , Sulfetos/química
13.
Biosci Trends ; 14(1): 23-34, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32092745

RESUMO

The roots of Angelica dahurica have long been used as a traditional medicine in Korea to treat various diseases such as toothache and cold. In this study, we investigated the effect of ethanol extract from the roots of this plant on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells and B16F10 cell inoculated-C57BL/6 mice. Our results showed that the ethanol extracts of Angelicae dahuricae Radix (EEAD) suppressed cell growth and induced apoptotic cell death in B16F10 cells. EEAD also activated the mitochondria-mediated intrinsic apoptosis pathway, with decreased mitochondrial membrane potential, and increased production of intracellular reactive oxygen species and ration of Bax/Bcl-2 expression. Furthermore, EEAD reduced the migration, invasion, and colony formation of B16F10 cells through the reduced expression and activity of matrix metalloproteinase (MMP)-2 and -9. In addition, in vivo results demonstrated that oral administration of EEAD inhibited lactate dehydrogenase activity, hepatotoxicity, and nephrotoxicity without weight loss in B16F10 cell inoculated-mice. Importantly, EEAD was able to markedly suppress lung hypertrophy, the incidence of B16F10 cells lung metastasis, and the expression of tumor necrosis factor-alpha in lung tissue. Taken together, our findings suggest that EEAD may be useful for managing metastasis and growth of malignant cancers, including melanoma.


Assuntos
Angelica/química , Melanoma Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Apoptose , Linhagem Celular Tumoral , Hipertrofia , L-Lactato Desidrogenase/antagonistas & inibidores , Pulmão/patologia , Neoplasias Pulmonares , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Metástase Neoplásica/prevenção & controle , Raízes de Plantas/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
Int J Nanomedicine ; 15: 1205-1214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110017

RESUMO

Background: Celastrol (CEL), a triterpene extracted from the Chinese herb tripterygium wilfordii, has been reported to have profound anticancer activities. However, poor water solubility and high side toxicities have severely restricted the clinical applications of CEL. Purpose: We proposed a facile "in situ drug conjugation-induced self-assembly" strategy to prepare CEL-loaded nanoparticles (CEL-NPs) that exhibited enhanced antitumor activity against melanoma. Methods: First, the CEL was chemically conjugated onto a methoxyl poly(ethylene glycol)-b-poly(L-lysine) (mPEG-PLL) backbone, resulting in the conversion of the double hydrophilic mPEG-PLL polymer into an amphiphilic polymer prodrug, mPEG-PLL/CEL. The obtained mPEG-PLL/CEL could self-assemble into stable micelles in aqueous solution due to the hydrophobic association of CEL moieties in the side chains and the possible electrostatic interaction between the carboxyl group in CEL and the residue amine group in the PLL segment. Thus, the obtained mPEG-PLL/CEL nanoparticles were named CEL self-stabilized nanoparticles (CEL-NPs), which were then characterized by dynamic light scattering and transmission electron microscopy. Furthermore, the antitumor effects of the CEL-NPs were investigated by an MTT assay in vitro and in a B16F10 tumor-bearing mice model. Results: The CEL-NPs exhibited sustained drug release behavior and were effectively endocytosed by B16F10 cells. Furthermore, the in vivo antitumor evaluation demonstrated that the CEL-NPs had remarkably higher tumor growth inhibition rates and lower systemic side effects than free CEL. Conclusion: In summary, our present work not only demonstrates the generation of stable CEL-loaded nanoparticles for the efficient treatment of melanoma but also describes a general way to prepare drug self-stabilized nanomedicine for anticancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Nanopartículas/química , Triterpenos/administração & dosagem , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Preparações de Ação Retardada , Difusão Dinâmica da Luz , Interações Hidrofóbicas e Hidrofílicas , Masculino , Melanoma , Camundongos Endogâmicos C57BL , Micelas , Microscopia Eletrônica de Transmissão , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Polilisina/análogos & derivados , Polilisina/química , Triterpenos/farmacocinética
15.
Nat Commun ; 11(1): 437, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974367

RESUMO

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/patologia , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Linfócitos T Reguladores/patologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/fisiologia
16.
Nat Biotechnol ; 38(3): 320-332, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932728

RESUMO

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.


Assuntos
Adjuvantes Imunológicos/química , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Camundongos , Nanopartículas , Medicina de Precisão , Primatas , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Vacinação , Vacinas Conjugadas
17.
Biomater Sci ; 8(4): 1106-1116, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31994549

RESUMO

In this study, we sought to design a bionanomaterial that could exert anticancer effects against primary tumors and protect against rechallenged tumors via photodynamic immunotherapy. As a biomaterial, we used an amphiphilic phenylalanine derivative of poly-gamma glutamic acid, which forms nanoparticles by self-assembly. For anticancer effects, we co-entrapped hydrophobic chlorin e6 and monophosphoryl lipid A in the core of the plain amphiphilic phenylalanine nanoparticles (AN), to generate M/C/AN. For comparison, we used plain AN and chlorin e6-loaded AN (C/AN). In vitro studies showed that B16F10 cancer cells treated with C/AN or M/C/AN generated reactive oxygen species and exhibited an enhanced surface display of calreticulin upon exposure to 660 nm light irradiation. C/AN and M/C/AN exerted similar photodynamic anticancer effects; however, M/C/AN, but not C/AN, induced in vitro dendritic cell maturation. Our biodistribution study revealed that C/AN and M/C/AN showed higher accumulation at the tumor tissues compared to that seen in the free chlorin e6-treated group. In B16F10 tumor-bearing mice, the intravenous injection of C/AN or M/C/AN showed similar photodynamic anticancer effects against primary tumors. However, the growth of rechallenged tumors was more significantly inhibited in the M/C/AN group compared to the C/AN group. At day 40 after inoculation of the primary tumor, M/C/AN-treated mice showed 100% survival, whereas the other groups showed 0% survival. In the tumor microenvironment, higher infiltration of CD8+ T cells was observed in the M/C/AN group compared to the other groups. Our results suggest that AN co-loaded with a photosensitizer and an immune stimulant may hold great potential for use in photodynamic immunotherapy to inhibit both primary and metastatic tumors.


Assuntos
Biomimética/métodos , Lipídeo A/análogos & derivados , Melanoma Experimental/tratamento farmacológico , Porfirinas/administração & dosagem , Administração Intravenosa , Animais , Cápsulas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoterapia , Lipídeo A/administração & dosagem , Lipídeo A/química , Lipídeo A/farmacocinética , Lipídeo A/farmacologia , Melanoma Experimental/imunologia , Camundongos , Nanopartículas , Fotoquimioterapia , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/química , Polímeros/química , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos
18.
Eur J Med Chem ; 186: 111878, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757524

RESUMO

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Fígado/química , Fígado/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/síntese química , Piperazinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
19.
Int J Cancer ; 146(5): 1409-1420, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702822

RESUMO

Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAFV600E mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-γ, TNF-α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Imiquimode/farmacologia , Imiquimode/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Camundongos , Mutação , Células T Matadoras Naturais , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo
20.
Eur J Med Chem ; 186: 111831, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740052

RESUMO

Heparanase is regarded as a promising target for anticancer drugs and Ronepastat is one of the most promising heparanase inhibitors insert in clinical study for Multiple Myeloma Therapy. To improve its pharmacokinetic/pharmacodynamic profile, as well to have an antidote able to neutralize its activity in case of over dosages or intolerance, a new class of its derivatives was obtained inserting non-carbohydrate moieties of different length between the polysaccharide chain and biotin or its derivatives. In vitro these novel derivatives maintain the anti-heparanase activity without induced toxicity. The newly synthesized compounds retained the ability to attenuate the growth of CAG myeloma tumors in mice with potency similar, or in one case even higher than that of the reference compound Roneparstat as well as inhibited metastatic dissemination (lung colonization) of murine B16-F10 melanoma cells in vivo.


Assuntos
Antineoplásicos/farmacologia , Biotina/química , Glucuronidase/antagonistas & inibidores , Glicóis/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Heparina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glucuronidase/metabolismo , Glicóis/síntese química , Glicóis/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Imagem Óptica , Relação Estrutura-Atividade
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