RESUMEN
Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
Asunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Imidazoles/síntesis química , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa del Receptor AxlRESUMEN
Combination therapy in Type 2 Diabetes Mellitus is necessary to achieve tight glycaemic control and reduce complication risk. Current treatment plans require patients to take several drugs concomitantly leading to low therapy adherence. This study describes the development and characterisation of a stable parenteral co-formulation of a sodium glucose co-transporter 2 inhibitor (dapagliflozin) and a therapeutic lipidated peptide, using hydroxypropyl-ß-cyclodextrin as an enabling excipient. Using NMR, calorimetry, computational modelling and spectroscopic methods, we show that besides increasing the solubility of dapagliflozin, cyclodextrin prevents self-association of the peptide through interaction with the lipid chain and amino acids prone to aggregation including aromatic groups and ionisable residues. While those interactions cause a dramatic secondary structure change, no impact on potency was seen in vitro. A subcutaneous administration of the co-formulation in rat showed that both drugs reach exposure levels previously shown to be efficacious in clinical mono-therapy studies. Interestingly, a faster absorption rate was observed for the peptide formulated within the cyclodextrin vehicle with respect to the buffer vehicle, which could trigger an earlier onset of action. The cyclodextrin based co-formulation is therefore a promising approach to develop a fixed dose combination of a therapeutic peptide and a small molecule drug for increased patient adherence and better blood glucose control.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Compuestos de Bencidrilo/farmacocinética , Glucemia/efectos de los fármacos , Excipientes/química , Glucósidos/farmacocinética , Hipoglucemiantes/farmacocinética , Péptidos/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Animales , Compuestos de Bencidrilo/química , Glucemia/metabolismo , Células CHO , Cricetulus , Combinación de Medicamentos , Composición de Medicamentos , Absorción Gastrointestinal , Glucósidos/química , Hipoglucemiantes/química , Inyecciones Subcutáneas , Masculino , Péptidos/administración & dosificación , Péptidos/química , Agregado de Proteínas , Estructura Secundaria de Proteína , Ratas , Inhibidores del Cotransportador de Sodio-Glucosa 2/química , SolubilidadRESUMEN
Recently developed drug delivery nanosystems, such as lipid nanocapsules (LNCs), hold great promise for the treatment of glioblastomas (GBs). In this study, we used a subpopulation of human mesenchymal stem cells, "marrow-isolated adult multilineage inducible" (MIAMI) cells, which have endogenous tumor-homing activity, to deliver LNCs containing an organometallic complex (ferrociphenol or Fc-diOH), in the orthotopic U87MG GB model. We determined the optimal dose of Fc-diOH-LNCs that can be carried by MIAMI cells and compared the efficacy of Fc-diOH-LNC-loaded MIAMI cells with that of the free-standing Fc-diOH-LNC system. We showed that MIAMI cells entrapped an optimal dose of about 20 pg Fc-diOH per cell, with no effect on cell viability or migration capacity. The survival of U87MG-bearing mice was longer after the intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells than after the injection of Fc-diOH-LNCs alone. The greater effect of the Fc-diOH-LNC-loaded MIAMI cells may be accounted for by their peritumoral distribution and a longer residence time of the drug within the tumor. These results confirm the potential of combinations of stem cell therapy and nanotechnology to improve the local tissue distribution of anticancer drugs in GB.
Asunto(s)
Antineoplásicos , Compuestos Ferrosos , Glioblastoma/terapia , Lípidos , Trasplante de Células Madre Mesenquimatosas , Nanocápsulas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Compuestos Ferrosos/administración & dosificación , Compuestos Ferrosos/química , Compuestos Ferrosos/uso terapéutico , Compuestos Ferrosos/toxicidad , Humanos , Lípidos/administración & dosificación , Lípidos/química , Lípidos/uso terapéutico , Lípidos/toxicidad , Ratones , Nanocápsulas/administración & dosificación , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Nanocápsulas/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this work, a novel ferrocenyl complex (ansa-FcdiOH) was assessed for brain tumor therapy through stealth lipid nanocapsules (LNCs). Stealth LNCs, prepared according to a one-step process, showed rapid uptake by cancer cells and extended blood circulation time. The ferrocenyl complex was successfully encapsulated into these LNCs measuring 40 nm with a high loading capacity (6.4%). In vitro studies showed a potent anticancer effect of ansa-FcdiOH on 9L cells with a low IC50 value (0.1 µM) associated with an oxidative stress and a dose-dependent alteration of the cell cycle. Repeated intravenous injections of stealth ansa-FcdiOH LNCs in ectopic glioma bearing rats induced a significant tumor growth inhibition, supported by a reduced number of proliferative cells in tumors compared to control group. Additionally, no liver damage was observed in treated animals. These results indicated that stealth ansa-FcdiOH LNCs might be considered as a potential new approach for cancer chemotherapy. FROM THE CLINICAL EDITOR: In this study, a novel ferrocenyl complex was assessed for brain tumor therapy through stealth lipid nanocapsules, demonstrating no liver damage, and superior tumor volume reduction compared to saline and stealth lipid nanocapsules alone in an ectopic glioma model.
Asunto(s)
Compuestos Ferrosos/química , Compuestos Ferrosos/uso terapéutico , Glioma/tratamiento farmacológico , Nanocápsulas/química , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Portadores de Fármacos/química , Femenino , Nanomedicina , Ratas , Ratas Endogámicas F344 , Especies Reactivas de OxígenoRESUMEN
Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and their treatment are challenging due to the tumor heterogeneity. The high death rate and the limited systemic treatment options for TNBC necessitate the search for alternative chemotherapeutics. We previously found that FcOHTAM, an organometallic derivative of hydroxytamoxifen, showed in vitro a strong antiproliferative effect on various breast cancer cell lines, including MDA-MB-231 cells, the archetype of TNBC. In this study, we developed stealth FcOHTAM loaded lipid nanocapsules (LNCs) to further evaluate this novel drug on a TNBC xenografted model. Cell cycle analysis of MDA-MB-231 cells confirmed the preservation of the drug activity through LNCs causing a cycle arrest in phase S after 48 h exposure at the IC50 concentration (2 µm). Two intraperitoneal injections of FcOHTAM loaded LNCs (20 mg/kg) administered to luciferase-transfected MDA-MB-231 tumors bearing mice led to a marked delay in tumor growth. As a consequence, a significantly lower tumor volume was obtained at the end of the experiment with a difference of 36% at day 38 compared to the untreated group. These results represent the first evidence of an in vivo effect of FcOHTAM and ferrocenyl derivatives in general on xenografted breast tumors.
Asunto(s)
Nanocápsulas/química , Tamoxifeno/análogos & derivados , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Mediciones Luminiscentes , Ratones , Ratones SCID , Estructura Molecular , Tamoxifeno/administración & dosificación , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
Since the serependitous discovery of the cisplatin antiproliferative activity, many efforts have focused on the design of potent metal-based drugs for oncology therapies. A large number of these complexes have been evaluated in vitro and in vivo and some have reached clinical trials. However, while metallodrug chemistry has developed to an advanced level, these emerging therapeutics have encountered new hurdles including poor water solubility and pharmacological deficiencies. Today, solutions to overcome these issues do not lie in synthesizing new anticancer drugs but in finding suitable drug delivery strategies. Over the past decades, various delivery systems have been developed including prodrug, ligand design and nanocarriers aimed at enhancing the performance profile of these novel metallodrugs.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Metales/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Humanos , Metales/química , Estructura MolecularRESUMEN
In this study, a new active targeting strategy to favour ferrociphenol (FcdiOH) internalisation into brain tumour cells was developed by the use of lipid nanocapsules (LNCs) coated with a cell-internalising peptide (NFL-TBS.40-63 peptide) that interacts with tubulin-binding sites. In comparison, OX26 murine monoclonal antibodies (OX26-MAb) targeting transferrin receptors were also inserted onto the LNC surface. The incorporation of OX26 or peptide did not influence the in vitro antiproliferative effect of FcdiOH-LNCs on the 9L cells since their IC50 values were found in the same range. In vivo, intracerebral administration of OX26-FcdiOH-LNCs or peptide-FcdiOH-LNCs by convection enhanced delivery did not enhance the animal median survival time in comparison with untreated rats (25 days). Interestingly, intra-carotid treatment with peptide-FcdiOH-LNCs led to an ameliorated survival time of treated rats with the presence of animals surviving until days 35, 40 and 44. Such results were not obtained with OX26-MAbs, demonstrating the benefit of NFL-TBS.40-63 peptide as an active ligand for peripheral drug delivery to the brain tumours.