Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Resistencia a Antineoplásicos/genética , Regulación Leucémica de la Expresión Génica , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Animales , Antineoplásicos/farmacología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/patología , Técnicas de Cocultivo , Citarabina/farmacología , Humanos , Ratones , Ratones Endogámicos NOD , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Neuronas/metabolismo , Neuronas/patología , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recurrencia , Transducción de Señal , Trasplante Heterólogo , Microambiente Tumoral/genéticaRESUMEN
We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated.
Asunto(s)
Antineoplásicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Oro/metabolismo , Nanopartículas del Metal/administración & dosificación , Neoplasias/tratamiento farmacológico , ARN Mensajero/metabolismo , Células 3T3 , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Dasatinib/administración & dosificación , Dasatinib/farmacocinética , Portadores de Fármacos/farmacocinética , Oro/administración & dosificación , Células HEK293 , Humanos , Células K562 , Nanopartículas del Metal/química , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function-including recruitment of effector cells.
Asunto(s)
Carcinoma Pulmonar de Lewis/inmunología , Inflamación/prevención & control , Células Madre Mesenquimatosas/fisiología , Linfocitos T/inmunología , Microambiente Tumoral , Adenoviridae/genética , Animales , Citotoxicidad Inmunológica , Proteína Ligando Fas/genética , Proteína Ligando Fas/fisiología , Ratones , Linfocitos T/fisiologíaRESUMEN
Spontaneous mouse models of cancer show promise to more accurately recapitulate human disease and predict clinical efficacy. Transgenic mice or viral vectors have been required to generate spontaneous models of glioma, a lethal brain tumor, because nonviral gene transfer is typically transient. To overcome this constraint, we used the Sleeping Beauty transposable element to achieve chromosomal integration of human oncogenes into endogenous brain cells of immunocompetent mice. Genetically engineered, spontaneous brain tumors were induced with plasmid DNA in a matter of weeks in three separate mouse strains. The phenotype of tumors was influenced by the combination of oncogenes delivered, resembling human astrocytoma or glioblastoma in the majority of cases. At least five different genes can be cotransfected simultaneously including reporters, allowing measurement of tumor viability by in vivo imaging. This model can accelerate brain tumor research in a variety of ways such as generation of "humanized" models for high throughput drug screening and candidate gene validation with exceptional speed and flexibility.