RESUMO
Cancer remains one of the most important challenges in biomedical sciences. Chemotherapeutic agents are very potent molecules that exhibit a significant level of toxicity in numerous tissues of the body, particularly in those characterized by high proliferative activity, such as the bone marrow. The scenario is even more complex in the case of the central nervous system, and in particular brain tumors, where the blood brain barrier limits the efficacy of drug therapies. Integrins, transmembrane proteins widely expressed in different types of cancer (glioblastoma, melanoma, and breast cancer), regulate the angiogenic process and play a pivotal role in tumor growth and invasion. Here, we report a nanotechnology strategy based on the use of AuNPs decorated with an arginine-glycine-aspartic acid-like peptide for the diagnosis and treatment of cancer. Two hours after administration in mice, the accumulation of the peptide-decorated NPs in the subcutaneous tumor was â¼4-fold higher than that of uncoated particles and â¼1.4-fold higher than that of PEGylated particles. Also, in the case of the intracranial tumor model, interesting results were obtained. Indeed, 2 h after administration, the amount of peptide-decorated particles in the brain was 1.5-fold that of undecorated particles and 5-fold that of PEGylated particles. In conclusion, this preliminary study demonstrates the high potential of this carrier developed for diagnostic and therapeutic applications.
Assuntos
Ouro/química , Nanopartículas Metálicas/química , Nanomedicina/métodos , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Citometria de Fluxo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Integrina alfaVbeta3/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Polietilenoglicóis/químicaRESUMO
BACKGROUND: Allergic rhinitis (AR) is characterized by mucosal inflammation, driven by activated immune cells. Mast cells and TH2 cells might decrease epithelial barrier integrity in AR, maintaining a leaky epithelial barrier. OBJECTIVE: We sought to investigate the role of histamine and TH2 cells in driving epithelial barrier dysfunction in AR. METHODS: Air-liquid interface cultures of primary nasal epithelial cells were used to measure transepithelial electrical resistance, paracellular flux of fluorescein isothiocyanate-dextran 4 kDa, and mRNA expression of tight junctions. Nasal secretions were collected from healthy control subjects, AR patients, and idiopathic rhinitis patients and were tested in vitro. In addition, the effect of activated TH1 and TH2 cells, mast cells, and neurons was tested in vitro. The effect of IL-4, IL-13, IFN-γ, and TNF-α on mucosal permeability was tested in vivo. RESULTS: Histamine as well as nasal secretions of AR but not idiopathic rhinitis patients rapidly decreased epithelial barrier integrity in vitro. Pretreatment with histamine receptor-1 antagonist, azelastine prevented the early effect of nasal secretions of AR patients on epithelial integrity. Supernatant of activated TH1 and TH2 cells impaired epithelial integrity, while treatment with anti-TNF-α or anti-IL-4Rα monoclonal antibodies restored the TH1- and TH2-induced epithelial barrier dysfunction, respectively. IL-4, IFN-γ, and TNF-α enhanced mucosal permeability in mice. Antagonizing IL-4 prevented mucosal barrier disruption and tight junction downregulation in a mouse model of house dust mite allergic airway inflammation. CONCLUSIONS: Our data indicate a key role for allergic inflammatory mediators in modulating nasal epithelial barrier integrity in the pathophysiology in AR.
Assuntos
Citocinas/imunologia , Histamina/imunologia , Mucosa Nasal/imunologia , Rinite Alérgica/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/patologia , Rinite Alérgica/patologia , Células Th1/patologia , Células Th2/patologiaRESUMO
Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.
Assuntos
Albuminas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Paclitaxel/administração & dosagem , Administração por Inalação , Albuminas/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Composição de Medicamentos/métodos , Feminino , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Humanos , Lipídeos/química , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/farmacocinética , Polietilenoglicóis/química , Propriedades de Superfície , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
High-grade gliomas (HGG) are the most common and most aggressive intrinsic human brain tumors in adults. Galectin-1, a glycan-binding protein that is overexpressed in HGG, has been shown to contribute significantly to the aggressive nature of HGG. It is unknown whether increased galectin-1 expression levels are exclusively found at the tumor site or whether galectin-1 can also be detected in the serum of HGG patients. Galectin-1 serum levels were analyzed in a prospective dataset of 43 healthy controls and 125 patients with newly diagnosed or recurrent HGG. Samples were taken at the moment of surgical resection and/or 2-3 weeks after surgery. Galectin-1 serum levels were determined using an ELISA for galectin-1. Galectin-1 serum levels depended significantly on age and sex in the control group. Age- and sex-adjusted galectin-1 serum levels were significantly higher in all patient subgroups compared to healthy controls with a high discriminative ability that increased with age. We did not observe a significant decrease in the galectin-1 serum levels upon surgical resection of the tumor. Collectively, the data presented here may represent a first step to establish galectin-1 as a biomarker in HGG disease monitoring. Further longitudinal evaluation is required and ongoing to investigate the value of galectin-1 serum levels in HGG patients as an additional diagnostic marker, but more importantly as a predictor of treatment response and prognosis. Furthermore, galectin-1 serum levels could also provide an important tool for the identification of HGG patients that could benefit from galectin-1 directed therapies that are currently under development.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/diagnóstico , Galectina 1/sangue , Glioma/sangue , Glioma/diagnóstico , Adolescente , Adulto , Idoso , Encéfalo/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.
Assuntos
Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Células Dendríticas/imunologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada , Células Dendríticas/citologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Linfócitos T/imunologia , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM.
RESUMO
Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H2O2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.
Assuntos
Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Quimiocina CXCL1/genética , Quimiocinas CC/genética , Neutrófilos/imunologia , Animais , Animais Geneticamente Modificados , Apoptose , Linhagem Celular Tumoral , Quimiocina CCL2/imunologia , Quimiocina CXCL1/imunologia , Quimiocina CXCL10/imunologia , Quimiocinas CC/imunologia , Técnicas de Cocultura , Citotoxicidade Imunológica , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Melanócitos/imunologia , Melanócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neuroglia/imunologia , Neuroglia/patologia , Neutrófilos/citologia , Transdução de Sinais , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Peixe-ZebraRESUMO
In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.
Assuntos
Tratamento Farmacológico/métodos , Galectina 1/genética , Técnicas de Silenciamento de Genes , Glioblastoma/terapia , Imunoterapia/métodos , RNA Interferente Pequeno/administração & dosagem , Microambiente Tumoral/fisiologia , Administração Intranasal , Animais , Modelos Animais de Doenças , Camundongos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacosRESUMO
Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro-inflammatory M1-like macrophages in the early stages, followed by in situ repolarization to M2-like macrophages, which produced VEGF-A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti-CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences.
Assuntos
Vasos Sanguíneos/patologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Vasos Sanguíneos/anormalidades , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Modelos Animais de Doenças , Feminino , Glioma/irrigação sanguínea , Glioma/tratamento farmacológico , Glioma/mortalidade , Humanos , Fator Estimulador de Colônias de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-sis/genética , Temozolomida , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of â¼50 nm and a zeta potential of â¼-4 mV were prepared with an encapsulation efficiency of â¼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1ß, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Administração por Inalação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Dextranos/química , Liberação Controlada de Fármacos , Feminino , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Leucina/química , Neoplasias Pulmonares/metabolismo , Manitol/química , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Paclitaxel/química , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , PósRESUMO
: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8-CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. SIGNIFICANCE: Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL-mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell-based research for immunotherapy.
Assuntos
Células-Tronco Adultas/citologia , Células-Tronco Multipotentes/citologia , Linfócitos T Citotóxicos/citologia , Adulto , Células-Tronco Adultas/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores/metabolismo , Comunicação Celular , Proliferação de Células , Citotoxicidade Imunológica , Galectina 1/metabolismo , Humanos , Isoantígenos/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Células-Tronco Multipotentes/metabolismo , Perforina/metabolismo , Linfócitos T Citotóxicos/metabolismoRESUMO
Galectin-1 (Gal-1) is a naturally occurring galactose-binding lectin, which is overexpressed in glioblastoma multiforme (GBM). Gal-1 is associated with tumor progression, and is a potent immune suppressor in the tumor micro-environment. To inhibit Gal-1 in GBM, an effective therapy is required that reaches the central nervous system tumor, with limited systemic effects. In this study, we report for the first time that concentrated chitosan nanoparticle suspensions can deliver small interfering RNA (siRNA) into the central nervous system tumor within hours after intranasal administration. These nanoparticles are able to complex siRNA targeting Gal-1 to a high percentage, and protect them from RNAse degradation. Moreover, a successful intracellular delivery of anti-Gal-1 siRNA resulted in a decreased expression of Gal-1 in both murine and human GBM cells. Sequence specific RNAinterference, resulted in more than 50% Gal-1 reduction in tumor bearing mice. This study indicates that the intranasal pathway is an underexplored transport route for delivering siRNA-based therapies targeting Gal-1 in the treatment of GBM.
Assuntos
Neoplasias Encefálicas/terapia , Encéfalo/patologia , Quitosana/química , Galectina 1/genética , Glioblastoma/terapia , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Administração Intranasal , Animais , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodosRESUMO
Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.
RESUMO
Despite recent advances in tumor imaging and chemoradiotherapy, the median overall survival of patients diagnosed with glioblastoma multiforme does not exceed 15 months. Infiltration of glioma cells into the brain parenchyma, and the blood-brain barrier are important hurdles to further increase the efficacy of classic therapeutic tools. Local administration methods of therapeutic agents, such as convection enhanced delivery and intracerebral injections, are often associated with adverse events. The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain. This route will bypass the blood-brain barrier and limit systemic side effects. Upon presentation at the nasal cavity, pharmacological agents reach the brain via the olfactory and trigeminal nerves. Recently, formulations have been developed to further enhance this nose-to-brain transport, mainly with the use of nanoparticles. In this review, the focus will be on formulations of pharmacological agents, which increase the nasal permeation of hydrophilic agents to the brain, improve delivery at a constant and slow release rate, protect therapeutics from degradation along the pathway, increase mucoadhesion, and facilitate overall nasal transport. A mounting body of evidence is accumulating that the underexplored intranasal delivery route might represent a major breakthrough to combat glioblastoma.