RESUMO
Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NPâ¯+â¯Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18⯱â¯1.0% ID/g, Pâ¯<â¯.0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, Pâ¯<â¯.0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID , Polietilenoglicóis/uso terapêutico , RadioisótoposRESUMO
Hepatocellular carcinomas (HCCs) are highly vascularized neoplasms with poor prognosis. Nanomedicine possesses great potential to deliver therapeutics and diagnostics. The new aspect of this study is that we have monitored, for the first time, the Raman responses to microtubule targeted vascular disrupting agents (MTVDA), MTVDA encapsulated non-targeted, and targeted cetuximab polymeric nanocomplexes delivery of combinatorial therapeutics in HCC tumor tissues of mice. Biochemical differences majorly demarcated apoptotic lipid bodies, and characteristic amide-I features. HCC tumor and healthy liver tissues could be stratified. Raman spectroscopy served as an excellent, rapid, sensitive and cost-effective approach for anticancer nanomedicine distinct stratification of MTVDA encapsulated targeted cetuximab polymeric nanocomplex combinatorials, a significant potential for HCC therapeutic monitoring.
Assuntos
Antineoplásicos/química , Carcinoma Hepatocelular/tratamento farmacológico , Cetuximab/química , Neoplasias Hepáticas/tratamento farmacológico , Nanocápsulas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Apoptose , Carcinoma Hepatocelular/diagnóstico , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab/farmacologia , Composição de Medicamentos , Humanos , Lipídeos/química , Fígado , Neoplasias Hepáticas/diagnóstico , Camundongos , NanomedicinaRESUMO
Aim: Synthesis of poly-L-lactic acid nanoparticles comprising of microtubule-inhibitor docetaxel and tyrosine kinase inhibitor sorafenib (PLDS NPs) for hepatoma treatment. Materials & methods: PLDS NPs were prepared by the emulsion solvent evaporation method and the anticancer activity was evaluated in Huh7 hepatoma cells. Results: Real-time imaging of quantum dots incorporating poly-L-lactic acid nanoparticles showed a rapid internalization of the nanoparticles in Huh7 cells. PLDS NPs exerted stronger antiproliferative, apoptotic and antiangiogenic effects than free single drug counterparts. They strongly promoted microtubule bundling, multinucleation and increased mitotic index in Huh7 cells. They also inhibited the expression of pERK1/2, pAKT and cyclin D1. Conclusion: We developed a single-nanoscale platform for dual drug delivery and high-sensitivity quantum dots imaging for hepatoma treatment. [Formula: see text].
Assuntos
Carcinoma Hepatocelular/enzimologia , Microtúbulos/química , Nanopartículas/química , Polímeros/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Sorafenibe/farmacologia , Linhagem Celular Tumoral , Emulsões/química , Humanos , Microtúbulos/efeitos dos fármacos , Pontos QuânticosRESUMO
Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial's concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future.
Assuntos
Fototerapia/métodos , Vitamina E/química , Animais , Feminino , Ácido Fólico/química , Hemólise , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/química , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Espectrofotometria InfravermelhoRESUMO
In this paper, we report the preparation of LbL-nanoSraf (100-300nm) comprising of layer-by-layer (LbL) assembled polyelectrolytes dextran-sulfate/poly-l-arginine, with a multikinase inhibitor sorafenib (Sraf) encapsulated calcium carbonate (CaCO3) nanoparticles for oral cancer therapy in vitro. The zeta potential of LbL-nanoSraf exhibited a negative charge of the polyanionic dextran sulfate, which alternated with a positive charge of polycationic poly-l-arginine indicating a successful LbL assembly of the two polyelectrolyte bilayers on the CaCO3 nanoparticles. The LbL-nanoSraf exhibited an encapsulation efficiency of 61±4%. The LbL-nanoSraf was characterized using field-emission gun scanning electron microscopy, X-ray powder diffraction, atomic force microscopy and confocal laser scanning microscopy. Confocal laser scanning microscopy, flow cytometry and transmission electron microscopic investigations showed the internalization of LbL-nanoSraf in human oral cancer (KB) cells. The LbL-nanoSraf exhibited more potent antiproliferative, apoptotic and antimigratory activities in KB cells than the free drug Sraf. The findings could promote the application of nano-sized LbL assembled polyelectrolytes for the delivery of Raf-kinase inhibitors and provide mechanistic insights for oral cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Nanopartículas/química , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Polieletrólitos/química , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carbonato de Cálcio/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Sulfato de Dextrana/química , Portadores de Fármacos/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Cinética , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Nanopartículas/ultraestrutura , Niacinamida/química , Niacinamida/farmacologia , Peptídeos/química , Compostos de Fenilureia/química , Polieletrólitos/farmacologia , Inibidores de Proteínas Quinases/química , Sorafenibe , Eletricidade EstáticaRESUMO
Polymeric nanoassemblies represent an attractive strategy for efficient cellular internalization of microtubule targeted anticancer drugs. Using dynamic light scattering, zeta potential, transmission electron microscopy and scanning electron microscopy, the physical properties and surface morphology of microtubule-binding PEGylated PLGA assembled nanospheres (100-200 nm) were analyzed. The present approach leads to strong internalization as observed by confocal laser scanning microscopy and transmission electron microscopy in hepatocarcinoma cells. The effect of these nanoassemblies on microtubules and mitosis were explored using immunofluorescence microscopy. The effects of these nanoassemblies on cancer cell proliferation and cell death revealed their antitumor enhancing effects. Perturbation of the microtubule assembly, mitosis and nuclear modulations potentiated the antineoplastic effects delivered via nanospheres in hepatocarcinoma cells. The extensive biomolecular and physical characterizations of the synthesized nanoassemblies will help to design potent therapeutic materials and the present approach can be applied to deliver microtubule-targeted drugs for liver cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/farmacologia , Ácido Láctico/farmacologia , Microtúbulos/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Ácido Poliglicólico/farmacologia , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Estradiol/administração & dosagem , Humanos , Ácido Láctico/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Microtúbulos/metabolismo , Mitose/efeitos dos fármacos , Nanosferas/química , Nanosferas/ultraestrutura , Polietilenoglicóis/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
In this study, we have developed microtubule destabilizing agents combretastatin A4 (CA4) or 2-methoxyestradiol (2ME) encapsulated poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) nanocomplexes for targeted delivery to human hepatocellular carcinoma (HCC) cells. An epidermal growth factor receptor (EGFR) is known to be overexpressed in HCC cells. Therefore, the targeting moiety cetuximab (Cet), an anti-EGFR chimeric monoclonal antibody, is functionalized on the surface of these diblock copolymeric coronas. Cetuximab is associated with the extracellular domain of the EGFR; therefore, the uptake of the cetuximab conjugated nanocomplexes occurred efficiently in EGFR overexpressing HCC cells indicating potent internalization of the complex. The cetuximab targeted-PLGA-b-PEG nanocomplexes encapsulating CA4 or 2ME strongly inhibited phospho-EGFR expression, depolymerized microtubules, produced spindle abnormalities, stalled mitosis, and induced apoptosis in Huh7 cells compared to the free drugs, CA4 or 2ME. Further, the combinatorial strategy of targeted nanocomplexes, Cet-PLGA-b-PEG-CA4 NP and Cet-PLGA-b-PEG-2ME NP, significantly reduced the migration of Huh7 cells, and markedly enhanced the anticancer effects of the microtubule-targeted drugs in Huh7 cells compared to the free drugs, CA4 or 2ME. The results indicated that EGFR receptor-mediated internalization via cetuximab facilitated enhanced uptake of the nanocomplexes leading to potent anticancer efficacy in Huh7 cells. Cetuximab-functionalized PLGA-b-PEG nanocomplexes possess a strong potential for the targeted delivery of CA4 or 2ME in EGFR overexpressed HCC cells, and the strategy may be useful for selectively targeting microtubules in these cells.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Cetuximab/química , Cetuximab/farmacologia , Sistemas de Liberação de Medicamentos , Receptores ErbB/metabolismo , Nanocompostos/química , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Imunofluorescência , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Microtúbulos , Polietilenoglicóis/química , Poliglactina 910/química , Células Tumorais CultivadasRESUMO
INTRODUCTION: Embelia ribes or Embelia tsjeriam-cottam, more commonly known as vidanga, is a type of ayurvedic medicine that has been used to treat various diseases for a number of years. Bright orange embelin -rich fruits have been well established as ethnomedicinals, for a number of years with their pharmacological actions attributed to their hydroxybenzoquinone active constituent. Embelin has become known specifically for its antihelminthic and contraceptive use. AREAS COVERED: This drug evaluation provides a historical summary of embelin along with its therapeutic use, phytochemistry and toxicology. Embelin's pharmacotherapeutical properties are also discussed along with its molecular targets. It is hoped that this article will help to draw the attention of researchers and biopharmaceutical companies to the untapped potential in bioprospection for the development of new drugs. EXPERT OPINION: Embelin is the only known non-peptide small-molecule X-linked inhibitor of the apoptosis protein (XIAP) - an anti-apoptotic protein considered a promising cancer therapeutic target. Embelin acts as an NF-κB blocker and potential suppressor of tumorigenesis. It also exhibits potent cytotoxic, antioxidant and cancer chemopreventive effects. Given the potential uses of embelin, it is recommended that further investigations take place to properly explore its pharmacological and clinical effects.
Assuntos
Benzoquinonas , Animais , Benzoquinonas/química , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Benzoquinonas/toxicidade , Humanos , Fitoterapia , Resultado do TratamentoRESUMO
INTRODUCTION: Alginate microspheres are versatile tools for the delivery of a wide range of therapeutic biomacromolecules. This naturally occurring biopolymer has many unique properties making it an ideal candidate for tailoring with different composites of polymers leading to the formation of strong complexes for a broad range of applications. AREAS COVERED: This article overviews various types of composite alginate microspheres, methods of preparation, new technologies available, physico-chemical characteristics, controlled release profiles, applications and the future directions of composite alginate microsphere delivery system for biomacromolecules. EXPERT OPINION: Composite alginate microsphere systems are the ideal carriers for controlled delivery applications because of their ability to encapsulate a myriad of therapeutic drugs, proteins, enzymes, DNA, antisense oligonucleotides, vaccines, growth factors and chemokines as well as the ease of processing, mechanical properties, biocompatibility, high bioavailability, controlled release rates, stability, suitability for different administration modes, targeted/localized delivery of different agents and large-scale production with cost-effectiveness. This article presents updated information of applying microalginate-based technologies and tools in the biomedical field which will benefit research scientists and clinical physicians or biopharmaceutical industries keen in the development of application-based new therapeutic and diagnostic strategies for various diseases. Furthermore, this technology will play more important roles in biosensors, vaccination, tissue engineering, cancer chemotherapeutics and stem cell research.
Assuntos
Alginatos/química , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Microesferas , Animais , Disponibilidade Biológica , Portadores de Fármacos , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Preparações Farmacêuticas/administração & dosagemRESUMO
Embelin, an active constituent isolated from the fruits of Embelia tsjeriam cottam was investigated for its chemopreventive and hepatoprotective effects against N-nitrosodiethylamine (NDEA) induced liver preneoplasia or carbon tetrachloride (CCl4) induced liver damage. Rats received NDEA, 1 ppm/g b.w. in drinking water for 6 weeks or CCl4, 0.7 ml/kg i.p. once a week for 4 weeks and embelin 50 mg, 100 mg/kg b.w. orally prior, during and after exposure to NDEA/CCl4 for 20 or 5 weeks, respectively. Embelin treatment significantly prevented NDEA or CCl4 induced increase in biochemical marker enzymes: glutamate pyruvate transaminase, glutamate oxaloacetate transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, glutathione-S-transferase, lipid peroxidase as well as hypoproteinemia, hypoalbuminuria and glutathione depletion. This was further substantiated by marked decrease in incidence of preneoplastic foci, and inflammatory cells on histopathological and transmission electron microscopic analysis. The present study suggests embelin is a promising chemopreventive and hepatoprotective agent.
Assuntos
Anticarcinógenos/farmacologia , Antioxidantes/uso terapêutico , Benzoquinonas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Extratos Vegetais/farmacologia , Lesões Pré-Cancerosas/prevenção & controle , Animais , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dietilnitrosamina , Embelia , Frutas , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/ultraestrutura , Masculino , Camundongos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
Sida rhombifolia ssp. retusa is a well established drug in the Ayurvedic system of medicine used for antirheumatism and antiasthmatism. Inhibitory effects of S. rhombifolia ssp. retusa seed extract on DEN induced hepatocellular preneoplastic foci and carbon tetrachloride (CCl4) induced hepatotoxicity was investigated in rats. Rats received DEN, 1ppm/g b.w. in drinking water for 6 weeks or CCl(4), 0.7 ml/kg i.p. once a week for 4 weeks and seed extract 50 mg, 100 mg/kg b.w. orally prior, during and after exposure to DEN/CCl4 for 20 or 5 weeks, respectively. Treatment with seed extract significantly inhibited the increase in DEN/CCl(4) induced activities of pre-cancerous marker enzymes; gamma-glutamyl transpeptidase, glutathione-S-transferase, hepatotoxicity marker enzymes; glutamate pyruvate transaminase, glutamate oxaloacetate transaminase and alkaline phosphatase as well as lipid peroxidase. Depleted glutathione, protein and albumin levels were restored. Also, histopathological and transmission electron microscopic studies showed prevention of cellular degenerative changes. The chemopreventive and hepatoprotective potentials of seed extract are due to free radical scavenging activity and restoration of cellular structural integrity.