RESUMEN
Cancer is a life-threatening disease worldwide. Although several approaches, such as surgery, chemotherapy, and radiotherapy, have been proven effective for many patients in clinics, they usually suffer from drug resistance, severe toxic-side effects, patient discomfort, and sometimes, unsatisfactory efficacies. In recent years, phototherapy, as a less invasive but effective therapeutic method, has brought hope for cancer treatment. However, most reported photo-therapeutic agents are constructed using complex components with non-negligible toxicity risk, thus retarding the start of their clinical trials. To address this issue, herein, biocompatible photothermal/photodynamic dual-mode therapeutic nanoparticles (CBP NPs) were successfully designed and constructed based on the Food and Drug Administration (FDA)-approved ingredients, chlorin e6 (Ce6) and poly(dopamine) (PDA). Upon light irradiation, hyperthermia was induced and reactive oxygen species (ROS) were generated simultaneously by CBP NPs, contributing to synergistic phototherapy toward cancer. The in vitro and in vivo experiments have demonstrated well the antitumor effect of CBP NPs. More importantly, CBP NPs are completely harmless and degradable in vivo. Together, the CBP NPs developed by us are an ideal candidate for the enhanced phototherapy of tumors, which holds great potential for future clinical translation.
RESUMEN
The size and structural control of particulate carriers for imaging agents and therapeutics are constant themes in designing smart delivery systems. This is motivated by the causal relationship between geometric parameters and functionalities of delivery vehicles. Here, both in vitro and in vivo, the controlling factors for cytotoxicity, photothermal, and anti-tumor effects of biodegradable magnesium@poly(lactic-co-glycolic acid (Mg@PLGA) particulate carriers with different sizes and shell thicknesses are investigated. Mg@PLGA microspheres fabricated by microfluidic emulsification are shown to have higher Mg encapsulation efficiency, 87%, than nanospheres by ultrasonic homogenization, 50%. The photothermal and anti-tumor effects of Mg@PLGA spheres are found to be dictated by their Mg content, irrelevant to size and structural features, as demonstrated in both in vitro cell assays and in vivo mice models. These results also provide important implications for designing and fabricating stimuli-responsive drug delivery vehicles.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/terapia , Magnesio/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Células HeLa , Humanos , Magnesio/química , Magnesio/farmacología , Ratones , Técnicas Analíticas Microfluídicas , Microesferas , Nanopartículas , Tamaño de la Partícula , Fototerapia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Photothermal therapy has attracted extensive attentions in cancer treatment due to its precise spatial-temporal controllability, minimal invasiveness, and negligible side effects. However, two major deficiencies, unsatisfactory heat conversion efficiency and limited tissue penetration depth, hugely impeded its clinical application. In this work, hollow carbon nanosphere modified with polyethylene glycol-graft-polyethylenimine (HPP) was elaborately synthesized. The synthesized HPP owns outstanding physical properties as a photothermal agent, such as uniform core-shell structure, good biocompatibility and excellent heat conversion efficiency. Upon NIR-II laser irradiation, the intracellular HPP shows excellent photothermal activity towards cancer cell killing. In addition, depending on the large internal cavity of HPP, the extended biomedical application as drug carrier was also demonstrated. In general, the synthesized HPP holds a great potential in NIR-II laser-activated cancer photothermal therapy.
Asunto(s)
Materiales Biocompatibles , Carbono/química , Nanosferas/química , Fototerapia/métodos , Terapia Fototérmica , Animales , Portadores de Fármacos/química , Humanos , Neoplasias/terapia , PolietilenglicolesRESUMEN
In this work, we reported the synthesis of an engineered novel nanocarrier composed of biodegradable charged polyester vectors (BCPVs) and graphene quantum dots (GQDs) for pancreatic cancer (MiaPaCa-2 cells) therapy applications. Such a nanocarrier was utilized to co-load doxorubicin (DOX) and small interfering ribonucleic acid (siRNA), resulting in the formation of GQD/DOX/BCPV/siRNA nanocomplexes. The resulting nanocomplexes have demonstrated high stability in physiologically mimicking media, excellent K-ras downregulation activity, and effective bioactivity inhibition for MiaPaCa-2 cells. More importantly, laser light was used to generate heat for the nanocomplexes via the photothermal effect to damage the cells, which was further employed to trigger the release of payloads from the nanocomplexes. Such triggered release function greatly enhanced the anticancer activity of the nanocomplexes. Preliminary colony formation study also suggested that GQD/DOX/BCPV/siRNA nanocomplexes are qualified carrier candidates in subsequent in vivo tests.
Asunto(s)
Grafito/química , Nanopartículas/química , Neoplasias Pancreáticas/terapia , Fototerapia , Plásticos Biodegradables/química , Plásticos Biodegradables/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Grafito/uso terapéutico , Humanos , Luz , Neoplasias Pancreáticas/patología , Polímeros/química , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéuticoRESUMEN
In this work, we report the engineering of polyelectrolyte polymers coated Gold nanorods (AuNRs)-based nanocarriers that are capable of co-delivering small interfering RNA (siRNA) and an anticancer drug doxorubicin (DOX) to Panc-1 cancer cells for combination of both chemo- and siRNA-mediated mutant K-Ras gene silencing therapy. Superior anticancer efficacy was observed through synergistic combination of promoted siRNA and DOX release upon irradiating the nanoplex formulation with 665 nm light. Our antitumor study shows that the synergistic effect of AuNRs nanoplex formulation with 665 nm light treatment is able to inhibit the in vivo tumor volume growth rate by 90%. The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells. Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments. The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Oro/administración & dosificación , Luz , Neoplasias Pancreáticas/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Femenino , Humanos , Hipertermia Inducida/métodos , Ratones Desnudos , Nanotubos , Fototerapia/métodos , Resultado del TratamientoRESUMEN
AIM: To investigate the effect of polydatin (PD), a resveratrol glucoside, on mast cell degranulation and anti-allergic activity. METHODS: After the rats were orally sensitized with ovalbumin (OVA) for 48 d and underwent PD treatment for 4 d, all the rats were stimulated by 100 mg/mL OVA for 24 h and then sacrificed for the following experiments. The small intestines from all the groups were prepared for morphology examination by hematoxylin and eosin staining. We also used a smooth muscle organ bath to evaluate the motility of the small intestines. The OVA-specific immunoglobulin E (IgE) production and interleukin-4 (IL-4) levels in serum or supernatant of intestinal mucosa homogenates were analyzed by enzyme-linked immunosorbent assay (ELISA). Using toluidine blue stain, the activation and degranulation of isolated rat peritoneal mast cells (RPMCs) were analyzed. Release of histamine from RPMCs was measured by ELISA, and regulation of PD on intracellular Ca(2+) mobilization was investigated by probing intracellular Ca(2+) with fluo-4 fluorescent dye, with the signal recorded and analyzed. RESULTS: We found that intragastric treatment with PD significantly reduced loss of mucosal barrier integrity in the small intestine. However, OVA-sensitization caused significant hyperactivity in the small intestine of allergic rats, which was attenuated by PD administration by 42% (1.26 ± 0.13 g vs OVA 2.18 ± 0.21 g, P < 0.01). PD therapy also inhibited IgE production (3.95 ± 0.53 ng/mL vs OVA 4.53 ± 0.52 ng/mL, P < 0.05) by suppressing the secretion of Th2-type cytokine, IL-4, by 34% (38.58 ± 4.41 pg/mL vs OVA 58.15 ± 6.24 pg/mL, P < 0.01). The ratio of degranulated mast cells, as indicated by vehicles (at least five) around the cells, dramatically increased in the OVA group by 5.5 fold (63.50% ± 15.51% vs phosphate-buffered saline 11.15% ± 8.26%, P < 0.001) and fell by 65% after PD treatment (21.95% ± 4.37% vs OVA 63.50% ± 15.51%, P < 0.001). PD mediated attenuation of mast cell degranulation was further confirmed by decreased histamine levels in both serum (5.98 ± 0.17 vs OVA 6.67 ± 0.12, P < 0.05) and intestinal mucosa homogenates (5.83 ± 0.91 vs OVA 7.35 ± 0.97, P < 0.05). Furthermore, we demonstrated that administration with PD significantly decreased mast cell degranulation due to reduced Ca(2+) influx through store-operated calcium channels (SOCs) (2.35 ± 0.39 vs OVA 3.51 ± 0.38, P < 0.01). CONCLUSION: Taken together, our data indicate that PD stabilizes mast cells by suppressing intracellular Ca(2+) mobilization, mainly through inhibiting Ca(2+) entry via SOCs, thus exerting a protective role against OVA-sensitized food allergy.
Asunto(s)
Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Hipersensibilidad a los Alimentos/prevención & control , Glucósidos/farmacología , Glucósidos/uso terapéutico , Mastocitos/efectos de los fármacos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Femenino , Hipersensibilidad a los Alimentos/metabolismo , Hipersensibilidad a los Alimentos/fisiopatología , Histamina/metabolismo , Inmunoglobulina E/sangre , Interleucina-4/sangre , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatología , Mastocitos/metabolismo , Mastocitos/patología , Ovalbúmina/efectos adversos , Ratas , Ratas Endogámicas BNRESUMEN
Mast cells play a key role in the pathogenesis of asthma and are a promising target for therapeutic intervention in asthma. This study investigated the effects of polydatin (PD), a resveratrol glucoside, on mast cell degranulation upon cross-linking of the high-affinity IgE receptors (FcεRI), as well as the anti-allergic activity of PD in vivo. Herein, we demonstrated that PD treatment for 30 min suppressed FcεRI-mediated mast cell degranulation in a dose-dependent manner. Concomitantly, PD significantly decreased FcεRI-mediated Ca²âº increase in mast cells. The suppressive effects of PD on FcεRI-mediated Ca²âº increase were largely inhibited by using LaCl3 to block the Ca²âº release-activated Ca²âº channels (CRACs). Furthermore, PD significantly inhibited Ca²âº entry through CRACs evoked by thapsigargin (TG). Knocking down protein expression of Orai1, the pore-forming subunit of CRACs, significantly decreased PD suppression of FcεRI-induced intracellular Ca²âº influx and mast cell degranulation. In a mouse model of mast cell-dependent passive cutaneous anaphylaxis (PCA), in vivo PD administration suppressed mast cell degranulation and inhibited anaphylaxis. Taken together, our data indicate that PD stabilizes mast cells by suppressing FcεRI-induced Ca²âº mobilization mainly through inhibiting Ca²âº entry via CRACs, thus exerting a protective effect against PCA.