RESUMEN
Due to the unique microenvironment, nanoparticles cannot easily penetrate deeply into tumours, which decreases their therapeutic efficacy. Thus, new strategies should be developed to solve this problem and increase the efficacy of nanomedicine. In this study, gold nanoraspberries (GNRs) were constructed using ultrasmall gold nanospheres (UGNPs) with a matrix metalloproteinase (MMP)-2/9-sensitive peptide as a cross-linking agent. These UGNPs were then modified with trastuzumab (TRA) and mertansine derivatives (DM1) via the AuS bond. TRA targets the human epidermal growth factor receptor-2 (Her-2) which is overexpressed on Her-2+ breast cancer cells. The AuS bond in GNRs-DM1 can be replaced by the free sulfhydryl group of GSH, which could achieve GSH dependent redox responsive release of the drug. In the mouse model of Her-2+ breast cancer, a "positive feedback" triple enhanced penetration platform was construct to treat tumours. Firstly, near-infrared light-triggered photothermal conversion increased vascular permeability, resulting in nanoparticle penetration. Secondly, GNRs disintegrated into UGNPs in response to stimulation with MMPs. GNRs with larger particle sizes reached the tumour site through EPR effect and active targeting. Meanwhile, UGNPs with smaller particle sizes penetrated deeply into the tumour through diffusion. Thirdly, the UGNPs transformed activated cancer-associated fibroblasts to a quiescent state, which reduced intercellular pressure and promoted the penetration of the UGNPs into the interior of the tumour. In turn, an increase in the number of nanoparticles penetrating into the tumour led to a "positive feedback" loop of triple enhanced photothermal effects and further self-amplify the permeability in vivo. Interventional photothermal therapy (IPTT) was used to improve the therapeutic efficacy by reducing the laser power attenuation caused by percutaneous irradiation. The GNRs also showed excellent multimode imaging (computed tomography, photoacoustic imaging and photothermal imaging) capabilities and high anti-tumour efficacy due to efficient tumour targeting and triple enhanced deep penetration into the tumour site. Thus, these MMP-2/redox dual-responsive GNRs are promising carriers of drugs targeting human epidermal growth factor receptor 2+ breast cancer.
Asunto(s)
Nanosferas , Nanotubos , Animales , Línea Celular Tumoral , Retroalimentación , Oro/química , Ratones , Nanotubos/química , Fototerapia , Terapia FototérmicaRESUMEN
Presently, a combination of chemotherapy, radiotherapy, thermotherapy, and other treatments has become a hot topic of research for the treatment of cancer, especially lung cancer. In this study, novel hollow gold nanoparticles (HGNPs) were used as drug carriers, and in order to improve the targeting ability of HGNPs to a lung tumor site, polyoxyethylene sorbitol oleate (PSO) was chosen here as a target ligand since it can be specifically recognized by the low-density lipoprotein (LDL) receptor which is usually over expressed on A549 lung cancer cells. In this way, a PSO-modified doxorubicin-loaded HGNP drug delivery system (PSO-HGNPs-DOX) was constructed and its physicochemical properties, photothermal conversion ability, and drug release of PSO-HGNPs-DOX was investigated. Further, the effects of triple combination therapy, the intracellular uptake, and the ability to escape macrophage phagocytosis of PSO-HGNPs-DOX were also studied using A549 cells in vitro. In addition, an in vivo mouse model was also used to study the targeting of PSO-HGNPs-DOX to lung cancer. PSO-HGNPs-DOX demonstrated a good triple therapeutic effect for lung cancer (A549 cell viability was only 10% at 500 µM) by LDL receptor mediated endocytosis and was able to escape macrophage phagocytosis to enhance its accumulation at the target site. Therefore, PSO-HGNPs-DOX is a novel, safe, promising, and targeted drug carrier designed for triple combination lung cancer therapy which should be further studied for such applications.
Asunto(s)
Endocitosis/fisiología , Hexosas/administración & dosificación , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Fagocitosis/fisiología , Receptores de LDL/metabolismo , Células A549 , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endocitosis/efectos de los fármacos , Oro/administración & dosificación , Humanos , Neoplasias Pulmonares/terapia , Macrófagos/efectos de los fármacos , Nanopartículas del Metal/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fagocitosis/efectos de los fármacos , Terapia Fototérmica/métodos , Polietilenglicoles/administración & dosificación , Ratas , Receptores de LDL/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
A simple and efficient high-performance liquid chromatography method combined with chemical pattern recognition was established for quality evaluation of Mahonia bealei (Fort.) Carr. A common pattern of 30 characteristic peaks was applied for similarity analysis, hierarchical cluster analysis, principal component analysis, and partial least squares discriminant analysis in the 37 batches of M. bealei (Fort.) Carr. to discriminate wild M. bealei (Fort.) Carr., cultivated M. bealei (Fort.) Carr., and its substitutes. The results showed that partial least squares discriminant analysis was the most effective method for discrimination. Eight characteristics peaks with higher variable importance in projection values were selected for pattern recognition model. A permutation test and 26 batches of testing set samples were performed to validate the model that was successfully established. All of the training and testing set samples were correctly classified into three clusters (wild M. bealei (Fort.) Carr., cultivated M. bealei (Fort.) Carr., and its substitutes) based on the selected chemical markers. Moreover, 26 batches of unknown samples were used to predict the accuracy of the established model with a discrimination accuracy of 100%. The obtained results indicated that the method showed great potential application for accurate evaluation and prediction of the quality of M. bealei (Fort.) Carr.
Asunto(s)
Medicamentos Herbarios Chinos/análisis , Mahonia/química , Extractos Vegetales/análisis , Cromatografía Líquida de Alta Presión , Análisis Discriminante , Análisis de Componente PrincipalRESUMEN
Cancer is a kind of malignant diseases that threatens human health and the research application of anti-tumor drug therapeutics is growingly always been focused on. Many new compounds with great anticancer activity were synthesized but cannot be hard to be developed into clinical use due to its poor water solubility. Deoxypodophyllotoxin (DPT) is just an example. We develop lyophilized Deoxypodophyllotoxin (DPT) loaded polymeric micelles using methoxy polyethylene glycol-block-Poly (D, L-lactide) (mPEG-PLA). DPT-PM freeze-dried powder was successfully prepared using optimized formulation. mPEG-PLA was added to hydration media before hydrating as cryoprotectants. The freeze-dried powder exhibited white pie-solid without collapsing, and the particle size of DPT-PM reconstituted with water was about 20-35 nm. The entrapment efficiency of the reconstituted solution was 98%, which shows no differences with the micelles before lyophilization. In-vitro cytotoxicity and cellular uptake studies showed that DPT-PM has a higher degree of cytotoxicity comparing with DPT and mPEG-PLA micelles and uptake of mPEG-PLA was concentration and time-dependent. In vivo characterization of DPT-PM was done for pharmacokinetics behaviors, antitumor activity and safety. The obtained results showed significant improvement in plasma clearance bioavailability (p <0.05) and prolonged blood circulation time comparing with DPT-HP-ß-CD. Moreover, mPEG-PLA micelles had a better degree of anti-tumor efficacy, this was due to better accumulation of mPEG-PLA in tumor cell via enhanced permeability and retention (EPR) effect. Therefore, DPT-PM has great clinical value, and can be expected to be a novel antitumor preparation.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Medicamentos Herbarios Chinos/administración & dosificación , Nanopartículas , Podofilotoxina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Liofilización , Humanos , Masculino , Ratones , Ratones Desnudos , Micelas , Neoplasias/tratamiento farmacológico , Tamaño de la Partícula , Podofilotoxina/administración & dosificación , Podofilotoxina/farmacocinética , Podofilotoxina/farmacología , Poliésteres/química , Polietilenglicoles/química , Factores de Tiempo , Distribución TisularRESUMEN
Recent studies have indicated that multidrug resistance (MDR) can significantly limit the effects of conventional chemotherapy. In this study, PT (Pachymic acid and dehydrotumulosic acid) are the two major triterpenoid components purified and identified in P. cocos. A liposomal co-delivery system encapsulating doxorubicin (DOX) and PT was prepared. Notably, the mechanism of PT reversed P-glycoprotein (P-gp) mediated MDR mainly relied on the inhibition of the P-gp function, which further decreased the levels of P-gp and caveolin-1 proteins. In drug-resistant MCF cells, co-administration with 5⯵g/ml PT significantly enhanced sensitivity of DOX. Finally, liposome-mediated co-delivery with PT significantly improved the anti-tumor effect of DOX in tumor-bearing mice when compared to other single therapy groups. In conclusion, this study showed for the first time that DOX and PT act synergistically as an "all-in-one" treatment to reverse MDR during tumor treatment and, thus, should be studied further for a wide range of anti-cancer applications.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Nanopartículas , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/uso terapéutico , Extractos Vegetales/química , Extractos Vegetales/farmacología , Wolfiporia/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mahonia bealei (Fort.) Carr. (M. bealei) plays an important role in the treatment of many diseases. In the present study, a comprehensive method combining supercritical fluid chromatography (SFC) fingerprints and chemical pattern recognition (CPR) for quality evaluation of M. bealei was developed. Similarity analysis, hierarchical cluster analysis (HCA), principal component analysis (PCA) were applied to classify and evaluate the samples of wild M. bealei, cultivated M. bealei and its substitutes according to the peak area of 11 components but an accurate classification could not be achieved. PLS-DA was then adopted to select the characteristic variables based on variable importance in projection (VIP) values that responsible for accurate classification. Six characteristics peaks with higher VIP values (≥1) were selected for building the CPR model. Based on the six variables, three types of samples were accurately classified into three related clusters. The model was further validated by a testing set samples and predication set samples. The results indicated the model was successfully established and predictive ability was also verified satisfactory. The established model demonstrated that the developed SFC coupled with PLS-DA method showed a great potential application for quality assessment of M. bealei.
Asunto(s)
Berberis/química , Mahonia/química , Extractos Vegetales/química , Cromatografía Líquida de Alta Presión , Cromatografía con Fluido Supercrítico , Hojas de la Planta/química , Análisis de Componente PrincipalRESUMEN
One of the main challenges for immune checkpoint blockade antibodies lies in malignancies with limited T-cell responses or immunologically "cold" tumors. Inspired by the capability of fever-like heat in inducing an immune-favorable tumor microenvironment, mild photothermal therapy (PTT) is proposed to sensitize tumors to immune checkpoint inhibition and turn "cold" tumors "hot." Here we present a combined all-in-one and all-in-control strategy to realize a local symbiotic mild photothermal-assisted immunotherapy (SMPAI). We load both a near-infrared (NIR) photothermal agent IR820 and a programmed death-ligand 1 antibody (aPD-L1) into a lipid gel depot with a favorable property of thermally reversible gel-to-sol phase transition. Manually controlled NIR irradiation regulates the release of aPD-L1 and, more importantly, increases the recruitment of tumor-infiltrating lymphocytes and boosts T-cell activity against tumors. In vivo antitumor studies on 4T1 and B16F10 models demonstrate that SMPAI is an effective and promising strategy for treating "cold" tumors.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Hipertermia Inducida/métodos , Melanoma Experimental/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Línea Celular Tumoral , Terapia Combinada , Preparaciones de Acción Retardada , Geles , Humanos , Inmunoterapia , Verde de Indocianina/análogos & derivados , Verde de Indocianina/farmacología , Lípidos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Células 3T3 NIH , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The therapeutic application of deoxypodophyllotoxin (DPT) is limited due to its poor water solubility and stability. In the present study, the micelles assembled by the amphiphilic block copolymers (mPEG-PDLLA) were constructed to improve the solubility and safety of DPT for their in vitro and in vivo application. The central composite design was utilized to develop the optimal formulation composed of 1221.41 mg mPEG-PDLLA, the weight ratio of 1 : 4 (mPEG-PDLLA : DPT), 30 mL hydration volume and the hydration temperature at 40 °C. The results showed that the micelles exhibited uniformly spherical shape with the diameter of 20 nm. The drug-loading and entrapment efficiency of deoxypodophyllotoxin-polymeric micelles (DPT-PM) were about (20 ± 2.84)% and (98 ± 0.79)%, respectively, indicating that the mathematical models predicted well for the results. Compared to the free DPT, the cytotoxicity showed that blank micelles possessed great safety for Hela cells. In addition, the DPT loaded micelle formulation achieved stronger cytotoxicity at the concentration of 1 × 10-7 mol·L-1, which showed significant difference from free DPT (P < 0.05). In conclusion, the micelles were highly promising nano-carriers for the anti-tumor therapy with DPT.
Asunto(s)
Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Micelas , Podofilotoxina/análogos & derivados , Poliésteres/química , Polietilenglicoles/química , Antineoplásicos/química , Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos , Células HeLa , Humanos , Tamaño de la Partícula , Podofilotoxina/química , Podofilotoxina/toxicidad , Solubilidad , Propiedades de SuperficieRESUMEN
Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a "nanoswitch" for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo-chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a ξ potential of -29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR-responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic toxicity of the NPs presented in this study hold significant potential for future cancer treatment.
Asunto(s)
Doxorrubicina/administración & dosificación , Oro , Liposomas/química , Nanopartículas del Metal , Neoplasias Experimentales/terapia , Animales , Línea Celular Tumoral , Liberación de Fármacos , Femenino , Calor , Humanos , Hipertermia Inducida , Células MCF-7 , Ratones Desnudos , Fototerapia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To achieve enhanced physical stability of poly(ethylene glycol)-poly(d,l-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(l-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT-PCMs) were spherical, with uniform distribution and particle sizes of 36.3±0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT-PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers.
Asunto(s)
Portadores de Fármacos/química , Podofilotoxina/análogos & derivados , Ácido Poliglutámico/química , Polilisina/química , Animales , Portadores de Fármacos/administración & dosificación , Liberación de Fármacos , Medicamentos Herbarios Chinos , Concentración de Iones de Hidrógeno , Espectroscopía de Resonancia Magnética , Masculino , Micelas , Peso Molecular , Tamaño de la Partícula , Podofilotoxina/administración & dosificación , Podofilotoxina/farmacocinética , Poliésteres/química , Polietilenglicoles/química , Espectroscopía de Protones por Resonancia Magnética , Conejos , Ratas Sprague-Dawley , Electricidad Estática , TemperaturaRESUMEN
In this paper, the status of adjuvant standard for Chinese materia medica processing in the Chinese Pharmacopoeia 2015 edition, the National Specification of Chinese Materia Medica Processing, and the 29 provincial specification of Chinese materia medica was summarized, and the the status including general requirements, specific requirements, and quality standard in the three grade official specifications was collected and analyzed according to the "medicine-adjuvant homology" and "food-adjuvant homology" features of adjuvants. This paper also introduced the research situation of adjuvant standard for Chinese materia medica processing in China; In addition, analyzed and discussed the problems existing in the standard system of adjuvant for Chinese materia medica processing, such as lack of general requirements, low level of standard, inconsistent standard references, and lack of research on the standard, and provided suggestions for the further establishment of the national standards system of adjuvant for Chinese materia medica processing.
Asunto(s)
Adyuvantes Farmacéuticos/normas , Materia Medica/normas , Medicina Tradicional China/normas , ChinaRESUMEN
As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.