RESUMEN
Combination therapy in cancer therapy has been widely used for its positive attributes, such as minimizing the undesirable side effects of chemotherapies and enhancing the therapeutic effects on different cancers. Compared with free drugs crizotinib (CRZ) and gemcitabine (GEM), CRZ@GEM-NPs could remarkably improve the cytotoxicity for endometrial cancer (EC) cells (Ishikawa cells and KLE cells) after treatment with MTT assay. In this study, CRZ and GEM were conjugated to tri-block copolymer poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, known as NPs). The fabricated nanoparticles were characterized by the high-resolution transmission electron microscopy (HR-TEM), and the particles size and zeta potential were investigated by the dynamic light scattering analysis. Further, the morphological features of the EC cell lines were examined by the biochemical staining assays. Morphological changes in endometrial cells morphology revealed by nuclear fragmentation and nuclear condensation (the hallmarks of apoptosis) were noted upon treatment with CRZ@GEM-NPs to the Ishikawa and KLE cancer cells. In addition, resulting in the highest ratio of apoptosis and mitochondrial membrane potential shows the cell death through the mitochondrial membrane potential. In vivo, systemic toxicity studies showed no histological changes and substantial blood biochemical with the near-normal appearance of the organs upon treatment with CRZ@GEM-NPs. Overall, the targeted combination suitable therapeutic framework may be a promising candidate for improved EC therapy.
Asunto(s)
Neoplasias Endometriales , Nanopartículas , Crizotinib , Desoxicitidina/análogos & derivados , Portadores de Fármacos , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Poliésteres , Polietilenglicoles , Polímeros , GemcitabinaRESUMEN
Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy, and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free GEM and PT core and the macromolecular system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Desoxicitidina/análogos & derivados , Nanopartículas/química , Neoplasias Nasofaríngeas/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Química Farmacéutica , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Portadores de Fármacos/química , Liberación de Fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of Regorafenib (REGO) and Cisplatin (PT) exhibits a great anticancer potential, as REGO enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of REGO and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free REGO and PT core and the polymeric system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside REGO to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of REGO into PLGA NPs (REGO-PT NPs). Further, the morphology of REGO NPs, PT NPs, and REGO-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore REGO-PT NPs induced significant apoptosis in human lung A549 and ovarian A2780 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assayes (AO-EB, Nuclear Staining and Annexin V-FITC). In a xenograft model of lung cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable nursing care of nanotherapy. Highlights Dual drug delivery of Regorafenib (REGO) and Cisplatin (PT) exhibits a great anticancer potential, as REGO enhances the effect of PT treatment of human cells by providing stability of the microenvironment. REGO-PT NPs induced significant apoptosis in human lung A549 and ovarian A2780 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assayes. In a xenograft model of lung cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/administración & dosificación , Piridinas/administración & dosificación , Células A549 , Animales , Antineoplásicos/síntesis química , Cisplatino/síntesis química , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Nanopartículas/química , Compuestos de Fenilurea/síntesis química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/síntesis química , Piridinas/síntesis química , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The rapid development of nanobiotechnology has enabled progress in therapeutic cancer vaccines. These vaccines stimulate the host innate immune response by tumor antigens followed by a cascading adaptive response against cancer. However, an improved antitumor immune response is still in high demand because of the unsatisfactory clinical performance of the vaccine in tumor inhibition and regression. To date, a complicated tumor immunosuppressive environment and suboptimal design are the main obstacles for therapeutic cancer vaccines. The optimization of tumor antigens, vaccine delivery pathways, and proper adjuvants for innate immune response initiation, along with reprogramming of the tumor immunosuppressive environment, is essential for therapeutic cancer vaccines in triggering an adequate antitumor immune response. In this review, we aim to review the challenges in and strategies for enhancing the efficacy of therapeutic vaccines. We start with the summary of the available tumor antigens and their properties and then the optimal strategies for vaccine delivery. Subsequently, the vaccine adjuvants focused on the intrinsic adjuvant properties of nanostructures are further discussed. Finally, we summarize the combination strategies with therapeutic cancer vaccines and discuss their positive impact in cancer immunity.
Asunto(s)
Vacunas contra el Cáncer , Neoplasias , Adyuvantes Inmunológicos/uso terapéutico , Antígenos de Neoplasias , Vacunas contra el Cáncer/uso terapéutico , Humanos , Inmunoterapia , Neoplasias/terapiaRESUMEN
The combinational delivery of doxorubicin and curcumin in a physically loaded nanocarrier offers the benefits of enhanced therapeutic efficacy and reduced adverse effects, but this strategy often suffers from the slow drug release followed by delayed onset of pharmacological action. This work reported the hydrazone-linked polymer-curcumin conjugate micelles containing physically loaded doxorubicin to address this problem; the ester-linked conjugate micelles were produced as the control. The pH-labile spherical micelles were less than 100 nm with a loading at 9.3 ± 0.5% (w/w, Curcumin) and 2.5 ± 0.1(w/w, Doxorubicin). Both agents were released at a faster rate in the pH-labile micelles compared to the control. The confocal laser scanning microscopy revealed a time-dependent co-localization of both agents in HepG2 cells. The IC50 of pH-labile conjugate micelles without doxorubicin in HepG2 cells was 27.7 ± 5.3 (µM), whereas the co-loaded micelles was lowered to 10.8 ± 3.4 (µM) (Cur-equivalent dose). The combination index calculation demonstrated a synergistic action of both agents in the co-loading nanocarrier. The current work provided an efficient nanocarrier system to achieve rapid on-demand drug release without onset delay of therapeutic action, which might add value to the clinical translation of the combinational delivery systems.