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1.
Anticancer Res ; 40(10): 5371-5378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988856

RESUMO

BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/química
2.
Int J Nanomedicine ; 15: 5165-5177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764943

RESUMO

Background: The integration of NIR photothermal therapy and chemotherapy is considered as a promising technique for future cancer therapy. Hollow Prussian nanospheres have attracted much attention due to excellent near-infrared photothermal conversion effect and drug-loading capability within an empty cavity. However, to date, the hollow Prussian nanospheres have been prepared by a complex procedure or in organic media, and their shell thickness and size cannot be controlled. Thus, a simple and controllable route is highly desirable to synthesize hollow Prussian nanospheres with controllable parameters. Materials and Methods: Here, in our designed synthesis route, the traditional FeCl3 precursor was replaced with Fe2O3 nanospheres, and then the Prussian blue (PB) nanoparticles were engineered into hollow-structured PB (HPB) nanospheres through an interface reaction, where the Fe2O3 colloidal template provides Fe3+ ions. The reaction mechanism and control factors of HPB nanospheres were systematically investigated. Both in vitro and in vivo biological effects of the as-synthesized HPB nanospheres were evaluated in detail. Results: Through systematical experiments, a solvent-mediated interface reaction mechanism was put forward, and the parameters of HPB nanospheres could be easily adjusted by growth time and template size under optimal water and ethanol ratio. The in vitro tests show the rapid and remarkable photothermal effects of the as-prepared HPB nanospheres under NIR laser irradiation (808 nm). Meanwhile, HPB nanospheres also demonstrated a high DOX loading capacity of 440 mg g-1 as a drug carrier, and the release of the drug can be regulated by the heat from PB shell under the exposure of an NIR laser. The in vivo experiments confirmed the outstanding performance of HPB nanospheres in photothermal/chemo-synergistic therapy of cancer. Conclusion: A solvent-mediated template route was developed to synthesize hollow Prussian blue (HPB) nanospheres in a simple and controllable way. The in vitro and in vivo results demonstrate the as-synthesized HPB nanospheres as a promising candidate due to their low toxicity and high efficiency for cancer therapy.


Assuntos
Portadores de Fármacos/química , Ferrocianetos/química , Nanosferas/química , Fototerapia/métodos , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Compostos Férricos/química , Humanos , Hipertermia Induzida
3.
Proc Natl Acad Sci U S A ; 117(32): 19136-19140, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727893

RESUMO

Cooperativity enhances the responsiveness of biomolecular receptors to small changes in the concentration of their target ligand, albeit with a concomitant reduction in affinity. The binding midpoint of a two-site receptor with a Hill coefficient of 1.9, for example, must be at least 19 times higher than the dissociation constant of the higher affinity of its two binding sites. This trade-off can be overcome, however, by the extra binding energy provided by the addition of more binding sites, which can be used to achieve highly cooperative receptors that still retain high affinity. Exploring this experimentally, we have employed an "intrinsic disorder" mechanism to design two cooperative, three-binding-site receptors starting from a single-site-and thus noncooperative-doxorubicin-binding aptamer. The first receptor follows a binding energy landscape that partitions the energy provided by the additional binding event to favor affinity, achieving a Hill coefficient of 1.9 but affinity within a factor of 2 of the parent aptamer. The binding energy landscape of the second receptor, in contrast, partitions more of this energy toward cooperativity, achieving a Hill coefficient of 2.3, but at the cost of 4-fold poorer affinity than that of the parent aptamer. The switch between these two behaviors is driven primarily by the affinity of the receptors' second binding event, which serves as an allosteric "gatekeeper" defining the extent to which the system is weighted toward higher cooperativity or higher affinity.


Assuntos
Receptores de Superfície Celular/química , Sítios de Ligação , Doxorrubicina/química , Doxorrubicina/metabolismo , Cinética , Ligantes , Ligação Proteica , Receptores de Superfície Celular/metabolismo
4.
Int J Nanomedicine ; 15: 4431-4440, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606687

RESUMO

Introduction: Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used photothermal agent, IR820, and chemotherapeutic drug, doxorubicin hydrochloride (DOX), are both hydrophilic molecules that suffer from the drawbacks of a short circulation time, rapid elimination and off-target effects. Methods and Results: Herein, a novel nanodrug that combined HCC-targeted IR820 and DOX was developed based on excipient-free co-assembly. First, lactosylated IR820 (LA-IR820) was designed to target HCC. Then, the LA-IR820/DOX nanodrug (LA-IR820/DOX ND) was purely self-assembled without excipient assistance. The physicochemical properties and the chemo-photothermal antitumour activity of the excipient-free LA-IR820/DOX ND were evaluated. More importantly, the obtained LA-IR820/DOX ND exhibited 100% drug loading, remarkable HCC targeting and excellent antitumour efficacy. Conclusion: This excipient-free LA-IR820/DOX ND may be a promising candidate for the synchronous delivery and synergistic targeting of IR820 and DOX as a combined chemo-photothermal therapy.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Verde de Indocianina/análogos & derivados , Lactose/química , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Verde de Indocianina/uso terapêutico , Verde de Indocianina/toxicidade , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Nanopartículas/ultraestrutura
5.
AAPS PharmSciTech ; 21(5): 166, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504144

RESUMO

Our aim in this study was to clarify the combination anticancer effect of Noscapine (Nos) loaded in a polymeric nanocarrier with Doxorubicin (Dox) on breast cancer cells. Nanoprecipitation method was used to prepare methoxy polyethylene glycol (mPEG), poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) containing Nos. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize the prepared Nos NPs. The anticancer activity of Nos NPs alone and in combination with Dox was assessed on 4T1 breast cancer cell line and in mice model. Spherical-shaped Nos NPs were prepared, with size of 101 ± 4.80 nm and zeta potential of - 15.40 ± 1 mV. Fourier transform infrared (FTIR) spectroscopy results demonstrated that Nos chemical structure was kept stable during preparation process. However, differential scanning calorimetric (DSC) thermogram proved that crystalline state of Nos changed to amorphous state in Nos NPs. The entrapment efficacy % (EE%) and drug loading % (DL%) of Nos NPs were about 87.20 ± 3.50% and 12.50 ± 2.30%, respectively. Synergistic anticancer effects of Nos both in free form (in hydrochloride form, Nos HCl) and Nos NPs form with Dox hydrochloride (Dox HCl) were observed on 4T1 cells. Combination of Nos NPs and Dox HCl inhibited tumor growth (68.50%) in mice more efficiently than Nos NPs (55.10%) and Dox HCl (32%) alone. Immunohistochemical (IHC) analysis of the tumor tissues confirmed antiangiogenic effect of Nos NPs. The findings highlighted efficacy of Nos NPs alone and in combination with Dox HCl on breast cancer tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/química , Nanopartículas/química , Noscapina/química , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C
6.
Ultrasonics ; 108: 106198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32590261

RESUMO

Contrast-enhanced ultrasound (CEUS) is widely applied in cancer diagnosis clinically. However, the gas-filled contrast agents are unstable in the blood and exhibit shorter imaging time, which limit their clinical use. In this study, a diagnostic nanoparticle system was developed for dual-mode imaging (ultrasound and fluorescence), which after encapsulation with doxorubicin (DOX) demonstrated simultaneous therapeutic function towards cancer treatment. Thus, calcium carbonate (CaCO3) nanoparticles were encapsulated with doxorubicin (DOX) to obtain CaCO3-DOX. Under acidic conditions, it produced carbon dioxide (CO2) to enhance ultrasound imaging and increase the release of DOX. After intravenously injecting CaCO3-DOX to tumor-bearing mice, in the presence of an ultrasound field, CO2bubbles were sufficiently generated at the tumor tissues for echogenic reflectivity. Also, the indocyanine green (ICG) was encapsulated into CaCO3 nanoparticles, to further detect the tumor with fluorescence. The resultant theranostic nanoparticle system exhibited therapeutic efficacy towards tumour-bearing mice. Overall, this investigation provides an attractive strategy for dual-mode cancer diagnostics.


Assuntos
Carbonato de Cálcio/farmacologia , Doxorrubicina/farmacologia , Imagem Multimodal , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Ultrassonografia/métodos , Animais , Carbonato de Cálcio/química , Dióxido de Carbono/metabolismo , Linhagem Celular Tumoral , Meios de Contraste , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Fluorescência , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Microambiente Tumoral
7.
Artigo em Inglês | MEDLINE | ID: mdl-32361467

RESUMO

Antibody-Drug Conjugates (ADCs) consist of antibodies attached to cytotoxic small molecules or biological agents (i.e., payloads) through chemical linkers which may be cleavable or non-cleavable. The development of new ADCs is challenging, particularly the process of attaching the linker-payload construct to the antibody (i.e., the conjugation process). One of the major problems associated with conjugation is high hydrophobicity of the payload which can lead to low yields of the ADC through aggregation and/or lower than desired Drug-Antibody Ratios (DARs). We report here a UPLC-based assay that can be used to study the physicochemical properties of ADC payloads at an early stage of development, and to provide information on whether the hydrophilic-hydrophobic balance is suitable for conjugation or further physicochemical optimization is required. The assay is relatively simple to establish and should be of use to those working in the ADC area.


Assuntos
Bioensaio/métodos , Imunoconjugados/química , Espectrometria de Massas em Tandem/métodos , Calicheamicinas/química , Cromatografia Líquida de Alta Pressão , Doxorrubicina/química , Flurbiprofeno/química , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/química , Irinotecano/química , Cetoprofeno/química , Maitansina/química , Conformação Molecular , Norfloxacino/química , Pentaclorofenol/química , Multimerização Proteica , Relação Estrutura-Atividade , Tolnaftato/química
8.
Int J Nanomedicine ; 15: 2751-2764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368053

RESUMO

Introduction: A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer. Methods: The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect. Results: The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo. Discussion: Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.


Assuntos
Antineoplásicos/administração & dosagem , Dendrímeros/química , Portadores de Fármacos/administração & dosagem , Nylons/química , Transferrina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Dendrímeros/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Células Hep G2 , Histidina/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Oxirredução , Polietilenoglicóis/química , Succinimidas/química , Transferrina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Biomed Sci ; 27(1): 45, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32200762

RESUMO

BACKGROUND: Human platelets (PLT) and PLT-extracellular vesicles (PEV) released upon thrombin activation express receptors that interact with tumour cells and, thus, can serve as a delivery platform of anti-cancer agents. Drug-loaded nanoparticles coated with PLT membranes were demonstrated to have improved targeting efficiency to tumours, but remain impractical for clinical translation. PLT and PEV targeted drug delivery vehicles should facilitate clinical developments if clinical-grade procedures can be developed. METHODS: PLT from therapeutic-grade PLT concentrate (PC; N > 50) were loaded with doxorubicin (DOX) and stored at - 80 °C (DOX-loaded PLT) with 6% dimethyl sulfoxide (cryopreserved DOX-loaded PLT). Surface markers and function of cryopreserved DOX-loaded PLT was confirmed by Western blot and thromboelastography, respectively. The morphology of fresh and cryopreserved naïve and DOX-loaded PLT was observed by scanning electron microscopy. The content of tissue factor-expressing cancer-derived extracellular vesicles (TF-EV) present in conditioned medium (CM) of breast cancer cells cultures was measured. The drug release by fresh and cryopreserved DOX-loaded PLT triggered by various pH and CM was determined by high performance liquid chromatography. The thrombin activated PEV was analyzed by nanoparticle tracking analysis. The cellular uptake of DOX from PLT was observed by deconvolution microscopy. The cytotoxicities of DOX-loaded PLT, cryopreserved DOX-loaded PLT, DOX and liposomal DOX on breast, lung and colon cancer cells were analyzed by CCK-8 assay. RESULTS: 15~36 × 106 molecules of DOX could be loaded in each PLT within 3 to 9 days after collection. The characterization and bioreactivity of cryopreserved DOX-loaded PLT were preserved, as evidenced by (a) microscopic observations, (b) preservation of important PLT membrane markers CD41, CD61, protease activated receptor-1, (c) functional activity, (d) reactivity to TF-EV, and (e) efficient generation of PEV upon thrombin activation. The transfer of DOX from cryopreserved PLT to cancer cells was achieved within 90 min, and stimulated by TF-EV and low pH. The cryopreserved DOX-loaded PLT formulation was 7~23-times more toxic to three cancer cells than liposomal DOX. CONCLUSIONS: Cryopreserved DOX-loaded PLT can be prepared under clinically compliant conditions preserving the membrane functionality for anti-cancer therapy. These findings open perspectives for translational applications of PLT-based drug delivery systems.


Assuntos
Plaquetas/fisiologia , Criopreservação , Doxorrubicina/química , Vesículas Extracelulares/fisiologia , Células Neoplásicas Circulantes/metabolismo , Plaquetas/química , Humanos
10.
J Phys Chem Lett ; 11(4): 1357-1363, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32017568

RESUMO

Large doses of anticancer drugs entering cancer cell nuclei are found to be effective at killing cancer cells and increasing chemotherapeutic effectiveness. Here we report red-emissive carbon quantum dots, which can enter into the nuclei of not only cancer cells but also cancer stem cells. After doxorubicin was loaded at the concentration of 30 µg/mL on the surfaces of carbon quantum dots, the average cell viability of HeLa cells was decreased to only 21%, while it was decreased to 50% for free doxorubicin. The doxorubicin-loaded carbon quantum dots also exhibited a good therapeutic effect by eliminating cancer stem cells. This work provides a potential strategy for developing carbon quantum-dot-based anticancer drug carriers for effective eradication of cancers.


Assuntos
Carbono/química , Núcleo Celular/metabolismo , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Pontos Quânticos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Células HeLa , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Transplante Heterólogo
12.
Dalton Trans ; 49(7): 2209-2217, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32003374

RESUMO

Photothermal therapy (PTT) is a promising treatment for tumors due to its efficiency and non-invasiveness. However, during the PTT treatment, reactive oxygen species (ROS) are produced in response to hyperthermia and thus harm the neighboring normal cells. In this work, a multifunctional theranostic agent (Se@SiO2@Au-PEG/DOX NCs) was exploited to solve this problem by introducing selenium, which can efficiently prevent normal cells from oxidative damage by scavenging reactive oxygen species during photothermal therapy. In addition, the Se@SiO2@Au-PEG/DOX nanocomposites (NCs) not only exhibited excellent properties of combined chemo-thermal synergistic therapy, but also showed no appreciable toxicity towards normal tissues due to the protective effect for continuous release of selenium. Thus, the fabricated Se@SiO2@Au-PEG/DOX NCs provide an integrated solution to overcome the limitations of selenium and PTT, and demonstrate great prospects as a safe and highly reliable theranostic agent.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Fotoquimioterapia , Nanomedicina Teranóstica , Células A549 , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Doxorrubicina/síntese química , Doxorrubicina/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Ouro/farmacologia , Humanos , Camundongos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Selênio/química , Selênio/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia
13.
J Mol Model ; 26(3): 54, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32036483

RESUMO

Using molecular dynamics simulations, the adsorption and diffusion of doxorubicin drug molecules in boron nitride nanotubes are investigated. The interaction between doxorubicin and the nanotube is governed by van der Waals attraction. We find strong adsorption of doxorubicin to the wall for narrow nanotubes (radius of 9 Å). For larger radii (12 and 15 Å), the adsorption energy decreases, while the diffusion coefficient of doxorubicin increases. It does, however, not reach the values of pure water, as adsorption events still hinder the doxorubicin mobility. It is concluded that nanotubes wider than around 4 nm diameter can serve as efficient drug containers for targeted drug delivery of doxorubicin in cancer chemotherapy.


Assuntos
Compostos de Boro/química , Doxorrubicina , Sistemas de Liberação de Medicamentos , Modelos Químicos , Simulação de Dinâmica Molecular , Nanotubos/química , Doxorrubicina/química , Doxorrubicina/farmacocinética
14.
Carbohydr Polym ; 231: 115745, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888811

RESUMO

Hydrogels are promising carriers for the controlled drug delivery in response to the external stimuli such as pH and temperature. Here, a new hydrogel is designed and synthesized from the cross-linking of graphene, chitosan, and cellulose nanowhisker via Schiff base reaction by a synthetic dialdehyde. The hydrogel presented a flexible structure and responded to altering pH and adding the external stimuli such as benzaldehyde and amino acid cysteine. The synthesized hydrogel was stable under physiological conditions. In vivo test showed that the hydrogel is subcutaneously injectable. Three drug-loaded hydrogels were synthesized, and in vitro drug release study showed a pH-dependent release of drugs in PBS solution.


Assuntos
Curcumina/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Benzaldeídos/química , Celulose/química , Celulose/farmacologia , Quitosana/química , Curcumina/farmacologia , Cisteína/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Grafite/química , Humanos , Concentração de Íons de Hidrogênio , Nanoestruturas/química , Temperatura
15.
Chem Commun (Camb) ; 56(13): 2000-2003, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-31960848

RESUMO

Poor solid-tumor penetration of nanocarriers limits the drug efficacy. Herein, small-sized copolymeric nanoparticles are prepared for delivering the chemotherapeutic drug DOX into solid tumors deeply and releasing the drug effectively. These small-sized copolymeric nanoparticles represent substantial potential for clinical translation.


Assuntos
Nanopartículas/química , Polímeros/química , Animais , Sobrevivência Celular , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Células HeLa , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Tamanho da Partícula
16.
J Nanobiotechnology ; 18(1): 18, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964403

RESUMO

BACKGROUND: Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. RESULTS: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. CONCLUSIONS: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.


Assuntos
Antineoplásicos/química , Fibroblastos Associados a Câncer/efeitos dos fármacos , Nanopartículas Metálicas/química , Metástase Neoplásica/tratamento farmacológico , Ligas/química , Animais , Antineoplásicos/uso terapêutico , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Progressão da Doença , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Ouro/química , Humanos , Nanopartículas Metálicas/uso terapêutico , Camundongos Endogâmicos BALB C , Metástase Neoplásica/patologia , Transplante de Neoplasias , Prata/química , Microambiente Tumoral/efeitos dos fármacos
17.
Chemistry ; 26(11): 2470-2477, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31912555

RESUMO

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Nanocápsulas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Composição de Medicamentos/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Vitamina E/química , Vitamina E/metabolismo
18.
AAPS PharmSciTech ; 21(2): 42, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897882

RESUMO

Mesoporous carriers have been widely used to deliver anticancer drugs due to their unique characteristics. In this work, mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) with substantially similar and uniform particle size, specific surface area, and pore size were prepared to compare the photothermal effect, drug loading efficiencies (LE), and drug release properties. In order to improve the dispersion stability and biocompatibility of the carriers, MSN and MCN were grafted with PEG, respectively. The NIR-induced photothermal effect results indicated that MCN had a brilliant photothermal conversion efficiency due to its strong near-infrared absorption capacity, while MSN had no photothermal conversion capability. Moreover, LE of DOX in DOX/MCN-PEG reached 36.58%, higher than that in DOX/MSN-PEG, which was ascribed to non-covalent interaction of π-π stacking and electrostatic attraction. In addition, compared to DOX/MSN-PEG, DOX/MCN-PEG had a significantly increased release rate under NIR laser irradiation due to excellent photothermal conversion capability of MCN-PEG. Furthermore, cell viability assay and cellular uptake experiment results demonstrated that DOX/MCN-PEG showed a synergistic therapeutic effect in the combination of chemotherapy and phototherapy, with a combination index (CI) of 0.238.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbono/química , Nanopartículas/química , Dióxido de Silício/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Linhagem Celular , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Hemólise/efeitos dos fármacos , Humanos , Tamanho da Partícula , Polietilenoglicóis , Porosidade , Coelhos
19.
Carbohydr Polym ; 232: 115764, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952581

RESUMO

A new fully biodegradable "reverse" oligosaccharide-based amphiphilic graft copolymer structure with a hydrophobic backbone and hydrophilic side chains, poly(ε-caprolactone)-g-dextran (PCL-g-Dex) was synthetized. For this purpose, "clickable" propargylated PCL (PCL-yne) and azido-dextran (Dex-N3) were prepared to further synthesize PCL-g-Dex copolymer by a Huisgen's cycloaddition. This "reverse" copolymer architecture self-assembled in biodegradable nano-carriers, in the shape of dynamic polymeric micelles, and were loaded with doxorubicin (Dox) anti-cancer drug. Dox-loaded micelles showed different drug releases depending on the pH. Cytotoxicity tests showed that Dox-loaded micelles can selectively kill colon cancer cells (HCT-116) while they have no cytotoxic effect towards healthy cells (CCD-45SK). Fluorescent micelles based on FITC-labelled PCL-g-Dex copolymer were used for fluorescence imaging and flow cytometry assays. These experiments proved the effective and specific internalization of micelles by cancer cells, whereas healthy cells showed a very poor uptake. These results show that PCL-g-Dex micelles may be a promising Dox nano-carrier in cancer chemotherapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Dextranos/química , Doxorrubicina/farmacologia , Nanopartículas/química , Poliésteres/química , Antibióticos Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Micelas , Estrutura Molecular , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície
20.
Mater Sci Eng C Mater Biol Appl ; 108: 110460, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923975

RESUMO

Myelosuppression, gastrointestinal toxicity and hypersensitivities always accompany chemotherapy of osteosarcoma (OS). In addition, the intricate karyotype of OS, the lack of targeted antitumor drugs and the bone microenvironment that provides a protective alcove for tumor cells reduce the therapeutic efficacy of chemotherapy. Here, we developed a multifunctional bone cement loaded with Fe3O4 nanoparticles and the antitumor drug doxorubicin (DOX/Fe3O4@PMMA) for synergistic MH ablation and chemotherapy of OS. The localized intratumorally administered DOX/Fe3O4@PMMA can change from liquid into solid at the tumor site via a polyreaction. The designed multifunctional bone cement was constructed with Fe3O4 nanoparticles, PMMA, and an antitumor drug approved by the U.S. Food and Drug administration (FDA). The injectability, magnetic hyperthermia (MH) performance, controlled drug release profile, and synergistic therapeutic effect of DOX/Fe3O4@PMMA in vitro were investigated in detail. Furthermore, the designed DOX/Fe3O4@PMMA controlled the release of DOX, enhanced the apoptosis of OS tissue, and inhibited the proliferation of tumor cells, demonstrating synergistic MH ablation and chemotherapy of OS in vivo. The biosafety of DOX/Fe3O4@PMMA was also evaluated in detail. This strategy significantly reduced surgical time, avoided operative wounds and prevented patient pain, showing a great clinical translational potential for OS treatment.


Assuntos
Cimentos para Ossos , Neoplasias Ósseas/terapia , Hipertermia Induzida , Nanopartículas de Magnetita , Osteossarcoma/terapia , Animais , Cimentos para Ossos/química , Cimentos para Ossos/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Polimetil Metacrilato/química , Polimetil Metacrilato/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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