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1.
Mol Ther ; 32(6): 1895-1916, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38549376

RESUMEN

Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells. In preclinical rodent tumor models, chemically stabilized acylated small interfering RNAs (siRNAs) selectively silenced Stat3 mRNA in multiple relevant cell types, reduced STAT3 protein levels, and increased cytotoxic T cell infiltration. In a murine model of CPI-resistant pancreatic cancer, RNAi-mediated Stat3 silencing resulted in tumor growth inhibition, which was further enhanced in combination with CPIs. To further exemplify the utility of RNAi for cancer immunotherapy, this technology was used to silence Cd274, the gene encoding the immune checkpoint protein programmed death-ligand 1 (PD-L1). Interestingly, silencing of Cd274 was effective in tumor models that are resistant to PD-L1 antibody therapy. These data represent the first demonstration of systemic delivery of RNAi agents to the TME and suggest applying this technology for immuno-oncology applications.


Asunto(s)
Antígeno B7-H1 , Interferencia de ARN , ARN Interferente Pequeño , Factor de Transcripción STAT3 , Microambiente Tumoral , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Animales , Ratones , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Línea Celular Tumoral , Humanos , Microambiente Tumoral/inmunología , ARN Interferente Pequeño/genética , Inmunoterapia/métodos , Resistencia a Antineoplásicos/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Modelos Animales de Enfermedad , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/genética
2.
J Am Chem Soc ; 133(4): 728-31, 2011 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-21171597

RESUMEN

It is controversial whether organic fluorine can form energetically important hydrogen bonds in aqueous environments. We previously showed by NMR and molecular modeling that the unexpectedly high binding affinity of 2'F-ANA is largely due to a C-H···F-C pseudohydrogen bond at pyrimidine-purine steps. Comparisons of the melting of duplexes with identical sequence composition but a rearranged sequence confirm that energetically important fluorine-mediated pseudohydrogen bonding is in operation in these sequences. The effect is of particular importance when the H-bond donor (purine H8) is activated by the presence of fluorine at its own 2'-position. These results provide a rational method to increase the binding affinity of antisense oligonucleotides by placement of 2'F-ANA modifications at pyrimidine-purine steps.


Asunto(s)
Diseño de Fármacos , Oligonucleótidos/química , Agua/química , Secuencia de Bases , Enlace de Hidrógeno , Conformación de Ácido Nucleico , Desnaturalización de Ácido Nucleico , Oligonucleótidos/genética , Oligonucleótidos/metabolismo , Termodinámica , Temperatura de Transición
3.
Nucleic Acid Ther ; 24(5): 336-43, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25162466

RESUMEN

We have investigated, for the first time, short interfering duplexes containing arabinonucleotides (ANA; the 2'-stereoisomer of RNA), as well as combinations of ANA with RNA, and their 2'-fluorinated derivatives 2F-ANA and/or 2'F-RNA. The results show that ANA is especially well accommodated in the sense strand of small interfering RNA (siRNA) duplexes, which can be extensively modified with little effect on potency. Furthermore, combining ANA with RNA and 2'F-ANA in siRNA passenger strands, particularly in patterns that bias duplex thermal stability, produces duplexes with similar (and sometimes enhanced) potency compared with native siRNA. Effective patterns of modification were identified against firefly luciferase screens in HeLa cells and then applied to knockdown of down-regulated in renal cell carcinoma (DRR), a novel and clinically tractable target for the treatment of glioblastoma.


Asunto(s)
Arabinonucleotidos/genética , Luciferasas/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Nucleares/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Arabinonucleotidos/síntesis química , Arabinonucleotidos/metabolismo , Línea Celular Tumoral , Expresión Génica , Genes Reporteros , Genes Supresores de Tumor , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neuroglía/metabolismo , Neuroglía/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Conformación de Ácido Nucleico , ARN Interferente Pequeño/síntesis química , ARN Interferente Pequeño/metabolismo , Estereoisomerismo
4.
Chemistry ; 14(21): 6352-68, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18512830

RESUMEN

A universal building block for the convergent synthesis of a wide variety of different T-shaped ternary amphiphiles was developed and used for the synthesis of a series of new liquid-crystalline materials composed of a rigid biphenyl core with polar glycerol groups at both ends and linear or branched alkyl chains in a lateral position. In addition, compounds with bulky achiral (2,4,6-trimethylphenoxy, adamantane-1-carboxylate, benzoate) or chiral (menthyl or cholesteryl) substituents attached to the end of the lateral alkyl chain were also investigated. In all cases the lateral chains were connected to the aromatic core by an ether linkage. The effect of the ether linking unit on mesophase stability and mesophase type is discussed with respect to conformational effects. The liquid-crystalline phases were investigated by polarizing microscopy, calorimetry, and X-ray diffraction of surface aligned samples. Upon enlarging the lateral chains a series of different polygonal cylinder phases was observed, which were replaced by lamellar phases and a non-cylinder hexagonal columnar phase by further increasing the size of these substituents. Remarkably, only pentagonal, hexagonal, and giant hexagonal cylinder phases could be observed, whereas mesophases composed of cylinders with a smaller number of sides are missing. No distinct chirality effects were observed for the menthyl- and cholesteryl-substituted compounds. However, the rodlike shape of the polycyclic cholesteryl core leads to a unique phase structure combining an organization of the alicyclic cholesteryl cores perpendicular to the layer planes and the aromatic biphenyl cores parallel to the layer planes.

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