RESUMEN
Photodynamic therapy (PDT) has been applied in clinical treatment of tumors for a long time. However, insufficient supply of pivotal factors including photosensitizer (PS), light, and oxygen in tumor tissue dramatically reduces the therapeutic efficacy of PDT. Nanoparticles have received an influx of attention as drug carriers, and recent studies have demonstrated their promising potential to overcome the obstacles of PDT in tumor tissue. Physicochemical optimization for passive targeting, ligand modification for active targeting, and stimuli-responsive release achieved efficient delivery of PS to tumor tissue. Various trials using upconversion NPs, two-photon lasers, X-rays, and bioluminescence have provided clues for efficient methods of light delivery to deep tissue. Attempts have been made to overcome unfavorable tumor microenvironments via artificial oxygen generation, Fenton reaction, and combination with other chemical drugs. In this review, we introduce these creative approaches to addressing the hurdles facing PDT in tumors. In particular, the studies that have been validated in animal experiments are preferred in this review over proof-of-concept studies that were only performed in cells.
RESUMEN
BACKGROUND: Combination therapy using more than one drug can result in a synergetic effect in clinical treatment of cancer. For this, it is important to develop an efficient drug delivery system that can contain multiple drugs and provide high accumulation in tumor tissue. In particular, simultaneous and stable loading of drugs with different chemical properties into a single nanoparticle carrier is a difficult problem. RESULTS: We developed rhamnolipid-coated double emulsion nanoparticles containing doxorubicin and erlotinib (RL-NP-DOX-ERL) for efficient drug delivery to tumor tissue and combination chemotherapy. The double emulsion method enabled simultaneous loading of hydrophilic DOX and hydrophobic ERL in the NPs, and biosurfactant RL provided stable surface coating. The resulting NPs showed fast cellular uptake and synergetic tumor cell killing in SCC7 cells. In real-time imaging, they showed high accumulation in SCC7 tumor tissue in mice after intravenous injection. Furthermore, enhanced tumor suppression was observed by RL-NP-DOX-ERL in the same mouse model compared to control groups using free drugs and NPs containing a single drug. CONCLUSIONS: The developed RL-NP-DOX-ERL provided efficient delivery of DOX and ERL to tumor tissue and successful tumor therapy with a synergetic effect. Importantly, this study demonstrated the promising potential of double-emulsion NPs and RL coating for combination therapy.
Asunto(s)
Antineoplásicos , Emulsiones/química , Glucolípidos/química , Nanopartículas , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Quimioterapia Combinada , Clorhidrato de Erlotinib/química , Clorhidrato de Erlotinib/farmacocinética , Clorhidrato de Erlotinib/farmacología , Ratones , Nanopartículas/química , Nanopartículas/metabolismo , Imagen ÓpticaRESUMEN
In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects in vivo. These overall results suggest that in vitro screening of drugs based on CI values, mechanism studies in hypoxia, and real-time in vivo imaging are promising strategies in developing NPs for optimized combination therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Clorofila/análogos & derivados , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Tirapazamina/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Clorofila/farmacocinética , Clorofila/efectos de la radiación , Clorofila/uso terapéutico , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Quimioterapia , Gelatina/química , Luz , Ratones Endogámicos C3H , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Tirapazamina/farmacocinéticaRESUMEN
We used antioxidant-containing nanoparticles (NPs) to treat acute hearing loss. Alpha-lipoic acid (ALA) served as the antioxidant; we employed Pluronic F127 to fabricate NPs. In vitro, ALA-NPs protected cells of the organ of Corti in HEI-OC1 mice, triggering nuclear translocation of NRF2 and increases in the levels of antioxidant proteins, including Nrf2, HO-1, SOD-1, and SOD-2. In vivo, the hearing of mice that received ALA-NP injections into the middle ear cavity was better preserved after induction of ototoxicity than in control animals. The cochlear Nrf2 level increased in test mice, indicating that the ALA-NPs protected hearing via the antioxidant mechanism observed in vitro. ALA-NPs effectively protected against acute hearing loss by activating the Nrf2/HO-1 pathway.
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Pérdida Auditiva/tratamiento farmacológico , Nanopartículas/química , Poloxámero/química , Ácido Tióctico/administración & dosificación , Ácido Tióctico/uso terapéutico , Membrana Timpánica/patología , Animales , Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Modelos Animales de Enfermedad , Pérdida Auditiva/patología , Masculino , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Nanopartículas/ultraestructura , Ácido Tióctico/farmacologíaRESUMEN
We fabricated poly (ethylene glycol)-block-polycaprolactone (PEG-b-PCL) nanoemulsion for drug delivery and photodynamic therapy. PEG-b-PCL effectively stabilized the interface between water and soybean oil, and the resulting nanoemulsion was about 220.3 nm in diameter with spherical shape. For photodynamic therapy (PDT), chlorin e6 (Ce6) was loaded into the nanoemulsion as a photosensitizer (PS). These chlorin e6-loaded PEG-PCL nanoemulsions (Ce6-PCL-NEs) showed efficient cellular uptake and, upon laser irradiation, generated singlet oxygen to kill tumor cells. Particularly, Ce6-PCL-NEs showed prolonged blood circulation and about 60% increased tumor accumulation compared to free Ce6 after intravenous injection to 4T1 tumor-bearing mice. These results demonstrate the promising potential of Ce6-PCL-NEs for efficient PDT and in vivo drug delivery to tumor tissue.
Asunto(s)
Portadores de Fármacos/química , Emulsiones , Lactonas/química , Nanopartículas , Polietilenglicoles/química , Porfirinas/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Clorofilidas , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Emulsiones/química , Ratones , Modelos Animales , Nanopartículas/química , Nanopartículas/ultraestructura , Fotoquimioterapia , Porfirinas/química , Porfirinas/farmacocinética , Fármacos Sensibilizantes a Radiaciones/química , Distribución TisularRESUMEN
Electrically conductive materials provide a suitable platform for the in vitro study of excitable cells, such as skeletal muscle cells, due to their inherent conductivity and electroactivity. Here it is demonstrated that bioinspired electroconductive nanopatterned substrates enhance myogenic differentiation and maturation. The topographical cues from the highly aligned collagen bundles that form the extracellular matrix of skeletal muscle tissue are mimicked using nanopatterns created with capillary force lithography. Electron beam deposition is then utilized to conformally coat nanopatterned substrates with a thin layer of either gold or titanium to create electroconductive substrates with well-defined, large-area nanotopographical features. C2C12 cells, a myoblast cell line, are cultured for 7 d on substrates and the effects of topography and electrical conductivity on cellular morphology and myogenic differentiation are assessed. It is found that biomimetic nanotopography enhances the formation of aligned myotubes and the addition of an electroconductive coating promotes myogenic differentiation and maturation, as indicated by the upregulation of myogenic regulatory factors Myf5, MyoD, and myogenin (MyoG). These results suggest the suitability of electroconductive nanopatterned substrates as a biomimetic platform for the in vitro engineering of skeletal muscle tissue.
Asunto(s)
Diferenciación Celular , Conductividad Eléctrica , Desarrollo de Músculos , Nanopartículas/química , Acrilatos/farmacología , Animales , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Ratones , Microscopía Fluorescente , Desarrollo de Músculos/efectos de los fármacos , Nanopartículas/ultraestructura , Poliuretanos/farmacología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Cellular senescence is thought to be an important tumor suppression process in vivo. We have previously shown that p53 activation is necessary for CKII inhibition-mediated cellular senescence. Here, CKII inhibition induced acetylation of p53 at K382 in HCT116 and HEK293 cells. This acetylation event was suppressed by SIRT1 activation. CKIIα and CKIIß were co-immunoprecipitated with SIRT1 in a p53-independent manner. Maltose binding protein pull-down and yeast two-hybrid indicated that SIRT1 bound to CKIIß, but not to CKIIα. CKII inhibition reduced SIRT1 activity in cells. CKII phosphorylated and activated human SIRT1 in vitro. Finally, SIRT1 overexpression antagonized CKII inhibition-mediated cellular senescence. These results reveal that CKII downregulation induces p53 stabilization by negatively regulating SIRT1 deacetylase activity during senescence.
Asunto(s)
Quinasa de la Caseína II/genética , Senescencia Celular/genética , Regulación hacia Abajo/genética , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Acetilación/efectos de los fármacos , Quinasa de la Caseína II/deficiencia , Quinasa de la Caseína II/metabolismo , Senescencia Celular/efectos de los fármacos , Células HCT116 , Células HEK293 , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Lisina/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/genética , Estabilidad Proteica/efectos de los fármacos , Subunidades de Proteína/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Sirtuina 1/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/químicaRESUMEN
A methanol extract of Houttuynia cordata showed an inhibitory effect on mammalian DNA topoisomerase I. Two topoisomerase I inhibitory compounds were purified and identified as caffeic acid and quercitrin. Caffeic acid and quercitrin inhibited the activity of topoisomerase I with IC(50) values of about 0.15 and 0.05 mM, respectively. A concentration of 45 µM caffeic acid caused 50% growth inhibition in human leukaemia U937 cells, but not on those of normal fibroblast NIH3T3 cells. However, quercitrin mysteriously stimulated proliferation of U937 and NIH3T3 cells. Caffeic acid-induced cell death was characterised with the cleavage of poly (ADP-ribose) polymerase and procaspase-3, indicating that this inhibitor triggered apoptosis. The apoptotic induction by caffeic acid was also confirmed using flow cytometry analysis. Because DNA topoisomerase I is an important target for tumour chemotherapy, the present study suggests that caffeic acid, but not quercitrin, may function by suppressing oncogenic disease through the inhibition of cellular topoisomerase I activity.
Asunto(s)
Ácidos Cafeicos/aislamiento & purificación , Ácidos Cafeicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Medicamentos Herbarios Chinos/química , Quercetina/análogos & derivados , Animales , Ácidos Cafeicos/química , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Houttuynia , Humanos , Ratones , Células 3T3 NIH , Quercetina/química , Quercetina/aislamiento & purificación , Quercetina/farmacologíaRESUMEN
We have previously shown that the down-regulation of protein kinase CKII activity is tightly associated with cellular senescence of human fibroblast IMR-90 cells. Here, we examined the roles of p53 and p21(Cip1/WAF1) in senescence development induced by CKII inhibition using wild-type, isogenic p53-/- and isogenic p21-/- HCT116 human colon cancer cell lines. A senescent marker appeared after staining for senescence-associated beta-galactosidase activity in wild-type HCT116 cells treated with CKII inhibitor or CKIIalpha siRNA, but this response was almost abolished in p53- or p21(Cip1/WAF1)-null cells. Increased cellular levels of p53 and p21(Cip1/WAF1) protein occurred with the inhibition of CKII. CKII inhibition upregulated p53 and p21(Cip1/WAF1) expression at post-transcriptional level and transcription level, respectively. RB phosphorylation significantly decreased in cells treated with CKII inhibitor. Taken together, this study shows that the activation of the p53-p21(Cip1/WAF1) pathway acts as a major mediator of cellular senescence induced by CKII inhibition.