RESUMEN
A novel chemical-based orthogonal bioconjugation strategy to produce tri-functionalized nanoparticles (NPs) an chemotherapy drug, doxorubicin (DOX), a near-infrared cyanine dye (Cy7) and CRGDK homing peptide, a peptide specifically binds to neuropilin-1 (Nrp-1) overexpressed on triple negative breast cancer (TNBC) cells, has been validated. These theranostic NPs have been evaluated in vitro and in vivo using an orthotopic xenotransplant mouse model using TNBC cells. In vitro assays show that theranostic NPs improve the therapeutic index in comparison with free DOX. Remarkably, in vivo studies showed preferred location of theranostic NPs in the tumor area reducing the volume at the same level than free DOX while presenting lower side effects. This multifunctionalized theranostic nanodevice based on orthogonal conjugation strategies could be a good candidate for the treatment and monitoring of Nrp-1 overexpressing tumors. Moreover, this versatile nanodevice can be easily adapted to treat and monitor different cancer types by adapting the conjugation strategy.
Asunto(s)
Carbocianinas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Nanopartículas , Péptidos , Nanomedicina Teranóstica , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Carbocianinas/química , Carbocianinas/farmacología , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Nanopartículas/química , Nanopartículas/uso terapéutico , Proteínas de Neoplasias/metabolismo , Neuropilina-1/metabolismo , Péptidos/química , Péptidos/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this manuscript, we report the development of a versatile, robust, and stable targeting nanocarrier for active delivery. This nanocarrier is based on bifunctionalized polymeric nanoparticles conjugated to a monoclonal antibody that allows for active targeting of either (i) a fluorophore for tracking or (ii) a drug for monitoring specific cell responses. This nanodevice can efficiently discriminate between cells in coculture based on the expression levels of cell surface receptors. As a proof of concept, we have demonstrated efficient delivery using a broadly established cell surface receptor as the target, the epidermal growth factor receptor (EGFR), which is overexpressed in several types of cancers. Additionally, a second validation of this nanodevice was successfully carried out using another cell surface receptor as the target, the cluster of differentiation 147 (CD147). Our results suggest that this versatile nanocarrier can be expanded to other cell receptors and bioactive cargoes, offering remarkable discrimination efficiency between cells with different expression levels of a specific marker. This work supports the ability of nanoplatforms to boost and improve the progress towards personalized medicine.
Asunto(s)
Portadores de Fármacos , Nanopartículas , Línea Celular Tumoral , Técnicas de Cocultivo , Sistemas de Liberación de Medicamentos , PolímerosRESUMEN
Despite the large number of polymeric nanodelivery systems that have been recently developed, there is still room for improvement in terms of therapeutic efficiency. Most reported nanodevices for controlled release are based on drug encapsulation, which can lead to undesired drug leakage with a consequent reduction in efficacy and an increase in systemic toxicity. Herein, we present a strategy for covalent drug conjugation to the nanodevice to overcome this drawback. In particular, we characterize and evaluate an effective therapeutic polymeric PEGylated nanosystem for controlled pH-sensitive drug release on a breast cancer (MDA-MB-231) and two lung cancer (A549 and H520) cell lines. A significant reduction in the required drug dose to reach its half maximal inhibitory concentration (IC50 value) was achieved by conjugation of the drug to the nanoparticles, which leads to an improvement in the therapeutic index by increasing the efficiency. The genotoxic effect of this nanodevice in cancer cells was confirmed by nucleus histone H2AX specific immunostaining. In summary, we successfully characterized and validated a pH responsive therapeutic polymeric nanodevice in vitro for controlled anticancer drug release.