RESUMO
Identification of cancer metastatic sites is of importance for adjusting therapeutic interventions and treatment choice. However, identifying the location of metastatic lesions with easy accessibility and high safety is challenging. Here we demonstrate that cancer metastatic sites can be accurately detected by a triple targeting nanoprobe. Through coencapsulating molecular beacons probing a cancer biomarker (CXCR4 mRNA), a lung metastatic biomarker (CTSC mRNA), and a bone metastatic biomarker (JAG1 mRNA), the nanoprobe decorated by SYL3C conjugated hyaluronic acid and ICAM-1 specific aptamer conjugated hyaluronic acid can target diverse phenotyped circulating tumor cells (CTCs) during epithelial-mesenchymal and mesenchymal-epithelial transitions in whole blood for sensitive probing. The detection of CTCs from cancer patients shows that the nanoprobe can provide accurate information to distinguish different cancer metastasis statuses including nonmetastasis, lung metastasis, and bone metastasis. This study proposes an efficient screening tool for identifying the location of distant metastatic lesions via facile blood biopsy.
Assuntos
Células Neoplásicas Circulantes , Humanos , Ácido Hialurônico , Biomarcadores Tumorais/genética , Biópsia , RNA Mensageiro/genética , Metástase NeoplásicaRESUMO
Cytochrome C (Cytc) has received considerable attention due to its ability to induce tumor apoptosis and generate oxygen to improve photodynamic therapy (PDT) efficiency. However, the damage to normal tissues caused by nonspecific accumulation of Cytc limits its application. Herein, in order to reduce its toxicity to normal tissues while retaining its activity, a charge conversional biomimetic nanosystem (CA/Ce6@MSN-4T1) is proposed to improve the tumor targeting ability and realize controlled release of Cytc in the tumor microenvironment. This nanosystem is constructed by coating tumor cell membrane on mesoporous silica nanoparticles coloaded with a photosensitizer (chlorin e6, Ce6) and the citraconic anhydride conjugated Cytc (CA) for synergistic photodynamic/protein therapy. The coating of the tumor cell membrane endows the nanoparticles with homologous targeting ability to the same cancer cells as well as immune escaping capability. CA undergoes charge conversion in the acidic environment of the tumor to achieve a controlled release of Cytc. The released Cytc can relieve cellular hypoxia to improve the PDT efficiency of Ce6 and can induce programmed cell death. Both in vitro and in vivo studies demonstrated that CA/Ce6@MSN-4T1 can efficiently inhibit the growth of tumors through synergistic photodynamic/protein therapy, and meanwhile show reduced side effects on normal tissues.
RESUMO
The chemotherapeutic effectiveness of pancreatic ductal adenocarcinoma (PDAC) is severely hampered by insufficient intratumoral delivery of antitumor drugs. Here, we demonstrate that enhanced pancreatic cancer chemotherapy can be achieved by probiotic spore-based oral drug delivery system via gut-pancreas axis translocation. Clostridium butyricum spores resistant to harsh external stress are extracted as drug carriers, which are further covalently conjugated with gemcitabine-loaded mesoporous silicon nanoparticles (MGEM). The spore-based oral drug delivery system (SPORE-MGEM) migrates upstream into pancreatic tumors from the gut, which increases intratumoral drug accumulation by â¼3-fold compared with MGEM. In two orthotopic PDAC mice models, tumor growth is markedly suppressed by SPORE-MGEM without obvious side effects. Leveraging the biological contact of the gut-pancreas axis, this probiotic spore-based oral drug delivery system reveals a new avenue for enhancing PDAC chemotherapy.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Probióticos , Camundongos , Animais , Linhagem Celular Tumoral , Esporos Bacterianos , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Sistemas de Liberação de Medicamentos , Pâncreas/patologia , Neoplasias PancreáticasRESUMO
To study the heterogeneity of circulating tumor cells (CTCs) is of crucial importance to analyze cancer progression and metastasis. However, in situ detection of highly heterogeneous CTCs in peripheral blood still faces an elusive challenge. Here, we show direct detection of two metastasis-related mRNAs of diverse CTCs in whole blood by a triple-targeting nanoprobe. In the nanoprobe, two kinds of molecular beacons, MB1 to detect RPL15 mRNA and MB2 to detect E-cadherin (E-cad) mRNA, are loaded in a highly efficient delivery vector decorated with EpCAM-targeted SYL3C, EGFR-targeted CL4, and CD44-targeted hyaluronic acid chains to specifically deliver MB1/MB2 into epithelial, mesenchymal, and stem CTCs in unprocessed peripheral blood. The numbers of RPL15+ and E-cad+ CTCs are positively correlated with the metastasis stages of cancer patients. This study provides an effective strategy to realize direct observation on diverse metastasis-related genes in living CTCs with different phenotypes to provide accurate information on cancer heterogeneity and metastasis.
Assuntos
Caderinas , Células Neoplásicas Circulantes , Proteínas Ribossômicas , Antígenos CD , Biomarcadores Tumorais , Caderinas/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Humanos , Células Neoplásicas Circulantes/patologia , RNA Mensageiro/genética , Proteínas Ribossômicas/genéticaRESUMO
The potential toxicity of nanoparticles, especially for clinically applicable ones, has become a critical concern. Technologies that can in situ-evaluate the toxicity of nanoparticles with high sensitivity are urgently needed. In this study, a facile strategy was developed for sensitive detection on the nanotoxicity of nanoparticles with low toxicity or a low dose. A functional nanoprobe loaded with molecular beacons was constructed to realize in situ evaluation of the nanotoxicity through probing multiple miRNAs in nanoparticle-exposed living cells. Being composed of protamine complexed with molecular beacons for miRNA detection and decorated by TAT and KALA peptides, the dual-peptide functionalized nanoprobe can efficiently deliver molecular beacons into living cells to realize the real-time monitoring of early biomarkers (miR-21 and miR-221) to evaluate nanotoxicity. Using mesoporous silica nanoparticles (MSNs) with different surface modifications as typical representatives of low toxic nanoparticles, we demonstrate that our nanoprobe can sensitively detect miRNA changes in cells under diverse exposure conditions, that is, MSN-NH2 exhibits the strongest capability to upregulate miR-21 and miR-221, and the upregulation is exposure dose- and time-dependent. Our approach is much more sensitive as compared with conventional methods to study cytotoxicity such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell morphology observation, and reactive oxygen species (ROS) assay. This study paves a path for effective and facile nanotoxicity evaluation and provides insights into the biological impacts of MSNs.
Assuntos
MicroRNAs , Nanopartículas , MicroRNAs/genética , Nanopartículas/química , Nanopartículas/toxicidade , Peptídeos/toxicidade , Porosidade , Espécies Reativas de Oxigênio , Dióxido de Silício/química , Dióxido de Silício/toxicidadeRESUMO
Cell-cell fusion studies provide an experimental platform for evaluating disease progression and investigating cell infection. However, to realize sensitive and quantitative detection on cell-cell fusion is still a challenge. Herein, we report a facile molecular beacon (MB)-based method for precise detection on cell-cell fusion. By transfection of the spike protein (S protein) and enhanced green fluorescent protein (EGFP) in HEK 293 cells, the virus-mimicking fusogenic effector cells 293-S-EGFP cells were constructed to interact with target cells. Before mixing the effector cells with the target cells, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in 293-S-EGFP cells was silenced, and the MB for GAPDH mRNA detection was delivered into the GAPDH silenced 293-S-EGFP cells. Once cell-cell fusion occurred, MB migrated from the GAPDH silenced effector cells to the target cells and hybridized with GAPDH mRNA in the target cells to induce fluorescence emission. The cell-cell fusion can be easily visualized and quantitated by fluorescence microscopy and flow cytometry. The fluorescence intensity is strongly dependent on the number of fused target cells. This MB-based method can easily identify the differences in the cell fusions for various target cells with different angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) expression levels, resulting in dramatically different fluorescence intensities in fused target cells. Our study provides a convenient and efficient quantitative detection approach to study cell-cell fusion.
Assuntos
Fusão Celular , Humanos , Células HEK293 , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Transfecção , Citometria de Fluxo , RNA Mensageiro/genéticaRESUMO
Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H2O2) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.
Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio , Camundongos , Neoplasias/tratamento farmacológico , Estresse Oxidativo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.
Assuntos
Imunoterapia/métodos , Melanoma Experimental/terapia , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/uso terapêutico , Administração Cutânea , Animais , Células Apresentadoras de Antígenos/imunologia , Catálise , Melanoma Experimental/imunologia , Camundongos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/metabolismo , PolimerizaçãoRESUMO
Crystallization of active pharmaceutical ingredients (APIs) from the supercooled liquid state is an important issue in determining the stability of amorphous pharmaceutical dispersions. In the present study, the isothermal crystallization from the supercooled liquid state of the pharmaceutical compound nifedipine was investigated by both rheological and differential scanning calorimetry (DSC) measurements, and the crystallization kinetics was fitted to the Johnson-Mehl-Avrami (JMA) equation. Both the crystallization induction time and completion time from the two methods were used to construct the time-temperature-transformation (TTT) diagram for nifedipine. A model based on a modification of classical homogeneous nucleation and crystal growth theory was employed to fit the induction and completion time curves. Both DSC and rheological methods give similar results for the crystallization kinetics of the nifedipine. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σSL of nifedipine was estimated and the value was found to be consistent with prior results obtained from melting point depression measurements as a function of crystal size. Evidence is shown that for temperatures below 110 °C, at the early stage of nucleation, NIF first nucleates into the metastable ß'-form and later converts into the stable α-form during the isothermal crystallization. We are also able to report the heat of fusion of the γ'-NIF based on the calorimetric experiments.
Assuntos
Química Farmacêutica , Nifedipino/química , Reologia , Temperatura , Termodinâmica , CristalizaçãoRESUMO
Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calorimetric and rheometric measurements. The kinetics of isothermal crystallization from the induction time to the completion of crystallization can be described by the classic Johnson-Mehl-Avrami (JMA) equation. The time-temperature-transformation (TTT) diagrams were constructed for two time points-that of induction and that of completion of crystallization. The results show that the rheological measurement for GDC-0276 has a better overall sensitivity in detection of the early stage nucleation and, consequently, detects the onset of crystallization sooner than does the differential scanning calorimetry. Rheological measurements were also used to obtain the temperature dependence of the viscosity of GDC-0276 and the relevant parameters were used in a modified form of the JMA model to describe the temperature dependence of the crystal induction and completion times, that is, the TTT diagram for the material. In the modification, we assumed that the kinetics followed the viscosity to the 0.75 power as suggested by the recent work of Huang et al. (Huang, C., et al., J. Chem. Phys.2018,149, 054503). The relationship and the possible impact on crystallization kinetics of the break-down of the Stokes-Einstein relation in glass-forming liquids are discussed. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σSL was obtained for GDC-0276 and was compared with that obtained from the melting point depression measurements of the material confined in nanoporous glasses. The differences between the values from the two methods are discussed.
Assuntos
Azetidinas/química , Benzamidas/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Vidro/química , Cinética , Reologia/métodos , Temperatura , Termodinâmica , Temperatura de TransiçãoRESUMO
The glass transition temperature (Tg) of a binary miscible mixture of molecular glasses, termed a coamorphous glass, is often synergistically increased over that expected for an athermal mixture due to the strong interactions between the two components. This synergistic interaction is particularly important for the formulation of coamorphous pharmaceuticals since the molecular interactions and resulting Tg strongly impact stability against crystallization, dissolution kinetics, and bioavailability. Current models that describe the composition dependence of Tg for binary systems, including the Gordon-Taylor, Fox, Kwei, and Braun-Kovacs equations, fail to describe the behavior of coamorphous pharmaceuticals using parameters consistent with experimental ΔCP and Δα. Here, we develop a robust thermodynamic approach extending the Couchman and Karasz method through the use of activity coefficient models, including the two-parameter Margules, non-random-two-liquid (NRTL), and three-suffix Redlich-Kister models. We find that the models, using experimental values of ΔCP and fitting parameters related to the binary interactions, successfully describe observed synergistic elevations and inflections in the Tg versus composition response of coamorphous pharmaceuticals. Moreover, the predictions from the NRTL model are improved when the association-NRTL version of that model is used. Results are reported and discussed for four different coamorphous systems: indomethacin-glibenclamide, indomethacin-arginine, acetaminophen-indomethacin, and fenretinide-cholic acid.
Assuntos
Composição de Medicamentos/métodos , Temperatura de Transição , Varredura Diferencial de Calorimetria , Química Farmacêutica , Estabilidade de Medicamentos , Solubilidade , VitrificaçãoRESUMO
To enhance the specificity and sensitivity of molecular beacons (MBs) in detecting mRNA in living tumor cells, we introduced an aptamer (AS1411) to the delivery system of MBs to form an aptamer-decorated nanoprobe (ANP), which was prepared through self-assembly between AS1411-conjugated carboxymethyl chitosan (ACMC) with protamine sulfate (PS)/CaCO3/MB cores. Owing to the specific binding of AS1411 to nucleolin, which is overexpressed in tumor cell membranes and nuclei, an AS1411-decorated MB-delivery system leads to dramatically increased cell uptake of MBs for probing survivin mRNA and thus induces strong intracellular fluorescence emission in targeted tumorous cells and cell nuclei. Furthermore, we demonstrate that ANP can efficiently detect survivin mRNA in mitochondria. In other words, the effective delivery of MBs ensures the precise detection of mRNA distribution in diverse organelles. In addition, we evaluated the efficiency of ANP in probing tumor cells in simulated blood as well as in peripheral blood from a healthy donor and found that the nanoprobe can specifically deliver MBs to tumor cells and identify tumor cells in blood. The targeting delivery system we constructed holds promising applications in precise detection of subcellular distribution of mRNA in living tumor cells as well as in fluorescence-guided cancer detection in liquid biopsy technology. This study provides a facile strategy to effectively improve the specificity and sensitivity of conventional molecular beacons.
Assuntos
Aptâmeros de Nucleotídeos/química , Sistemas de Liberação de Medicamentos , Sondas Moleculares/análise , Quitosana/análogos & derivados , Quitosana/química , Células HeLa , Humanos , Células MCF-7 , Imagem MolecularRESUMO
By leveraging the ability of Shewanella oneidensis MR-1 (S.â oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, a lactate-fueled biohybrid (Bac@MnO2 ) was constructed by modifying manganese dioxide (MnO2 ) nanoflowers on the S.â oneidensis MR-1 surface. The biohybrid Bac@MnO2 uses decorated MnO2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make a complete bacterial respiration pathway at the tumor sites, which results in the continuous catabolism of intercellular lactate. Additionally, decorated MnO2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H2 O2 ) into generate oxygen (O2 ), which could prevent lactate production by downregulating hypoxia-inducible factor-1α (HIF-1α) expression. As lactate plays a critical role in tumor development, the biohybrid Bac@MnO2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.
Assuntos
Neoplasias do Colo/metabolismo , Compostos de Manganês/metabolismo , Óxidos/metabolismo , Shewanella/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Regulação para Baixo , Humanos , Peróxido de Hidrogênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Compostos de Manganês/química , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Óxidos/química , Oxigênio/metabolismo , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
The impact of nanoconfinement on the crystallization and glass transition behaviors of nifedipine (NIF) has been investigated using differential scanning calorimetry. Nanoconfinement was provided by imbibing the NIF into a porous medium (controlled pore glass, CPG), and results were compared with the unconfined bulk material. Consistent with previous results from the literature, both glass transition temperature Tg and melting temperature Tm decrease with decreasing pore size. The melting temperature was found to decrease with the reciprocal of pore diameter and could be analyzed with the Gibbs-Thomson equation. In addition, for confinement sizes of 7.5 and 12 nm, it was found that no cold-crystallization occurs upon heating from the glassy state to above the expected melting transition. Finally, at intermediate confinements we find evidence of a possible new, confinement-induced polymorph of NIF.
Assuntos
Cristalização/métodos , Vidro/química , Nifedipino/química , Temperatura , Termodinâmica , Temperatura de TransiçãoRESUMO
To efficiently deliver CpG oligodeoxynucleotides (ODNs) to macrophages for the reversal of cancer-induced immunosuppression, nanoparticles ODN@MCBSA with mannosylated cationic albumin (MCBSA) as a macrophage targeting vector were constructed. Compared with ODN@CBSA with cationic albumin (CBSA) as a vector, ODN@MCBSA exhibited significantly improved cellular uptake mediated by mannose moieties, resulting in significantly enhanced secretion of proflammatory cytokines including IL-12, IL-6, TNF-α, and iNOS. The modulation of macrophages toward the favorable M1 phenotype was confirmed by the upregulated CD80 expression after being treated by ODN delivery systems. In addition to immune cells, the effects of the ODN delivery system on cancerous HeLa cells were also investigated. The results showed that ODN@MCBSA did not affect the overall tumor cell viability. However, enhanced NF-κB, p-Akt, PIK3R3, Fas, and FasL, as well as upregulated caspases were observed in tumor cells, implying the pleiotropic effects on tumor cells. Our study provides a more in-depth understanding on the immunotherapeutic effects of CpG ODNs and highlights the importance of macrophage targeting delivery to minimize the effects on tumor cells. These results indicate that MCBSA could serve as a promising delivery vector of CpG ODNs to macrophages for cancer immunotherapy.
Assuntos
Macrófagos/metabolismo , Nanopartículas/química , Oligodesoxirribonucleotídeos/metabolismo , Células HeLa , Humanos , Interleucina-12/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
One of critical steps in genome editing by CRISPR-Cas9 is to deliver the CRISPR-Cas9 system into targeted cells. In this study, we developed a dual-targeting delivery system based on polymer/inorganic hybrid nanoparticles to realize highly efficient genome editing in targeted tumor cells as well as in situ detection on the related protein expression in edited cells. The CRISPR-Cas9 plasmid for CDK11 knockout was encapsulated in the core of the delivery system composed of protamine sulfate, calcium carbonate, and calcium phosphate by coprecipitation, and functional derivatives of carboxymethyl chitosan (biotinylated carboxymethyl chitosan with biotin ligands and aptamer-incorporated carboxymethyl chitosan with AS1411 ligands) were decorated on the nanovector surface by electrostatic interactions to form the dual-targeting delivery system. On the basis of the tumor cell targeting capability of biotin and AS1411 ligands as well as the nuclear targeting of AS1411, the dual-targeting system can deliver the CRISPR-Cas9 plasmid into the nuclei of tumor cells to realize highly efficient genome editing, resulting in a dramatic decrease (>90%) in CDK11 protein together with the significant downregulation of other proteins involved in tumor development, including an â¼90% decrease in MMP-9, >40% decrease in VEGF, and â¼70% decrease in survivin. Using the same vector, molecular beacons can be easily delivered to edited cell nuclei to in situ detect the mRNA level of related proteins (p53 and survivin as typical examples) and mRNA distribution in subcellular organelles. Our strategy can realize effective genome editing and in situ detection on related protein expression simultaneously.
Assuntos
Edição de Genes/métodos , Inativação Gênica , Transfecção/métodos , Biotina/química , Carbonato de Cálcio/química , Quitosana/análogos & derivados , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Células MCF-7 , Nanopartículas/química , Protaminas/químicaRESUMO
Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON-p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials.
Assuntos
Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Estruturas Metalorgânicas/administração & dosagem , Neoplasias/terapia , Polifenóis/química , Proteína Supressora de Tumor p53/genética , Antineoplásicos/farmacologia , Morte Celular , Linhagem Celular Tumoral , Genes p53 , Terapia Genética , Humanos , Estruturas Metalorgânicas/farmacologia , Nanoestruturas , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Plasmídeos , Propriedades de SuperfícieRESUMO
As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+ )-organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image-guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment.
Assuntos
Metais/química , Metástase Neoplásica/terapia , Polifenóis/farmacologia , Nanomedicina Teranóstica/métodos , Animais , Morte Celular , Movimento Celular , Ouro/química , Células HeLa , Humanos , Masculino , Metabolômica , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dióxido de Silício/químicaRESUMO
PURPOSE: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed. METHOD: To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells. RESULTS: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR). CONCLUSIONS: The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.
Assuntos
Antineoplásicos/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Biotina/química , Butionina Sulfoximina/administração & dosagem , Carbonato de Cálcio/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Sinergismo Farmacológico , Glutationa/metabolismo , Células HeLa , Heparina/química , Humanos , Células MCF-7 , Polímeros/química , Protaminas/química , Quinolinas/administração & dosagemRESUMO
Fighting metastasis is a major challenge in cancer therapy, and stimulation of the immune system is of particular importance in the treatment of metastatic cancers. Here, an integrated theranostic nanoplatform was developed for the efficient treatment of highly metastatic tumors. Versatile functions including "And" logically controlled drug release, prolonged circulation time, tumor targeting, and anti-metastasis were integrated into doxorubicin (DOX) loaded, highly integrated mesoporous silica nanoparticles (DOX@HIMSNs) for a systemic treatment of highly metastatic triple negative breast cancer (TNBC). It was found that the good therapeutic effect of DOX@HIMSN was only partially attributed to its anticancer cytotoxicity. Most importantly, DOX@HIMSN could induce anticancer immune responses including dendritic cell (DC) maturation and antitumor cytokine release. Compared with the traditional tumor chemotherapy, the integrated theranostic nanoplatform we developed not only improved the tumor specific cytotoxicity but also stimulated antitumor immune responses during the treatment.