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In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg-AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs. However, the endothelial cells remained unaffected under similar experimental conditions. The cellular internalization studies have indicated that EGCg-AuNPs internalize into the SMCs and ECs within short periods of time through laminin receptor mediated endocytosis mode. Favorable toxicity profiles and selective affinity toward SMCs and ECs suggest that EGCg-AuNPs may provide attractive alternatives to drug coated stents and therefore offer new therapeutic approaches in treating cardiovascular diseases.
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Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Catequina/análogos & derivados , Portadores de Fármacos/química , Ouro/química , Nanopartículas Metálicas/química , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacocinética , Catequina/administração & dosagem , Catequina/farmacocinética , Catequina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/prevenção & controle , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Receptores de Laminina/metabolismo , Proteínas RibossômicasRESUMO
Systemic delivery of therapeutic agents to solid tumors is hindered by vascular and interstitial barriers. We hypothesized that prostate tumor specific epigallocatechin-gallate (EGCg) functionalized radioactive gold nanoparticles, when delivered intratumorally (IT), would circumvent transport barriers, resulting in targeted delivery of therapeutic payloads. The results described herein support our hypothesis. We report the development of inherently therapeutic gold nanoparticles derived from the Au-198 isotope; the range of the (198)Au ß-particle (approximately 11 mm in tissue or approximately 1100 cell diameters) is sufficiently long to provide cross-fire effects of a radiation dose delivered to cells within the prostate gland and short enough to minimize the radiation dose to critical tissues near the periphery of the capsule. The formulation of biocompatible (198)AuNPs utilizes the redox chemistry of prostate tumor specific phytochemical EGCg as it converts gold salt into gold nanoparticles and also selectively binds with excellent affinity to Laminin67R receptors, which are over expressed in prostate tumor cells. Pharmacokinetic studies in PC-3 xenograft SCID mice showed approximately 72% retention of (198)AuNP-EGCg in tumors 24 h after intratumoral administration. Therapeutic studies showed 80% reduction of tumor volumes after 28 d demonstrating significant inhibition of tumor growth compared to controls. This innovative nanotechnological approach serves as a basis for designing biocompatible target specific antineoplastic agents. This novel intratumorally injectable (198)AuNP-EGCg nanotherapeutic agent may provide significant advances in oncology for use as an effective treatment for prostate and other solid tumors.
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Anticarcinógenos/farmacocinética , Catequina/análogos & derivados , Ouro/farmacocinética , Nanopartículas Metálicas , Neoplasias da Próstata/tratamento farmacológico , Animais , Anticarcinógenos/farmacologia , Catequina/farmacocinética , Catequina/farmacologia , Linhagem Celular Tumoral , Feminino , Ouro/farmacologia , Radioisótopos de Ouro/farmacocinética , Radioisótopos de Ouro/farmacologia , Humanos , Masculino , Camundongos , Camundongos SCID , Tamanho da Partícula , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Development of cancer receptor-specific gold nanoparticles will allow efficient targeting/optimum retention of engineered gold nanoparticles within tumors and thus provide synergistic advantages in oncology as it relates to molecular imaging and therapy. Bombesin (BBN) peptides have demonstrated high affinity toward gastrin-releasing peptide (GRP) receptors in vivo that are overexpressed in prostate, breast, and small-cell lung carcinoma. We have synthesized a library of GRP receptor-avid nanoplatforms by conjugating gold nanoparticles (AuNPs) with BBN peptides. Cellular interactions and binding affinities (IC(50)) of AuNP-BBN conjugates toward GRP receptors on human prostate cancer cells have been investigated in detail. In vivo studies using AuNP-BBN and its radiolabeled surrogate (198)AuNP-BBN, exhibiting high binding affinity (IC(50) in microgram ranges), provide unequivocal evidence that AuNP-BBN constructs are GRP-receptor-specific showing accumulation with high selectivity in GRP-receptor-rich pancreatic acne in normal mice and also in tumors in prostate-tumor-bearing, severe combined immunodeficient mice. The i.p. mode of delivery has been found to be efficient as AuNP-BBN conjugates showed reduced RES organ uptake with concomitant increase in uptake at tumor targets. The selective uptake of this new generation of GRP-receptor-specific AuNP-BBN peptide analogs has demonstrated realistic clinical potential in molecular imaging via x-ray computed tomography techniques as the contrast numbers in prostate tumor sites are severalfold higher as compared to the pretreatment group (Hounsfield unit = 150).
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Bombesina/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Neoplasias/metabolismo , Receptores da Bombesina/metabolismo , Animais , Bombesina/administração & dosagem , Bombesina/química , Bombesina/farmacocinética , Linhagem Celular Tumoral , Ouro/administração & dosagem , Ouro/farmacocinética , Humanos , Injeções Intraperitoneais , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos , Peso Molecular , Solubilidade/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose: We report an innovative green nanotechnology utilizing an electron-rich cocktail of phytochemicals from Yucca filamentosa L. to synthesize biocompatible gold nanoparticles without the use of any external chemical reducing agents and evaluate their anti-cancer activity. Methods: Yucca filamentosa L. extract, containing a cocktail of phytochemicals, was prepared, and used to transform gold salt into Y. filamentosa phytochemicals encapsulated gold nanoparticles (YF-AuNPs). Additionally, gum arabic stabilized YF-AuNPs (GAYF-AuNPs) were also prepared to enhance the in vitro/in vivo stability. Anticancer activity was evaluated against prostate (PC-3) and breast (MDAMB-231) cancer cell lines. Targeting abilities of gold nanoparticles were tested using pro-tumor macrophage cell lines. Results: Comprehensive characterization of new nanomedicine agents YF-AuNPs and GAYF-AuNPs revealed spherical, and monodisperse AuNPs with moderate zeta potentials (-19 and -20 mV, respectively), indicating in vitro/in vivo stability. The core size of YF-AuNPs (14 ± 5 nm) and GAYF-AuNPs (10 ± 5 nm) is suitable for optimal penetration into tumor cells through both enhanced permeability and retention (EPR) effect as well as through the receptor mediated endocytosis. Notably, YF-AuNPs exhibited potent anticancer activity against prostate (PC-3) and breast tumors (MDAMB-231) by inducing early and late apoptotic stages. Moreover, YF-AuNPs resulted in elevated levels of anti-tumor cytokines (TNF-α and IL-12) and reduced levels of pro-tumor cytokines (IL-6 and IL-10), provide compelling evidence on the immunomodulatory property of YF-AuNPs. Conclusion: Overall, these Y. filamentosa phytochemicals functionalized nano-Ayurvedic medicine agents demonstrated selective toxicity to cancer cells while sparing normal cells. Most notably, to our knowledge, this is the first study that shows YF-AuNP's targeting efficacy toward pro-tumor macrophage cell lines, suggesting an immunomodulatory pathway for cancer treatment. This work introduces a novel avenue for herbal and nano-Ayurvedic approaches to human cancer treatment, mediated through selective efficacy and immunomodulatory potential.
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TCN006, a formulation of (R)-3-Hydroxybutyrate glycerides, is a promising ingredient for enhancing ketone intake of humans. Ketones have been shown to have beneficial effects on human health. To be used by humans, TCN006 must be determined safe in appropriately designed safety studies. The results of a bacterial reverse mutation assay, an in vitro mammalian micronucleus study, and 14-and 90-day repeat dose toxicity studies in rats are reported herein. In the 14- and 90-day studies, male and female Wistar rats had free access to drinking water containing 0, 75,000, 125,000 or 200,000 ppm TCN006 for 92 and 93 days, respectively. TCN006 tested negative for genotoxicity and the no observed adverse effect level (NOAEL) for toxicity in the 14- and 90-day studies was 200,000 ppm, the highest dose administered. In the longer term study, the mean overall daily intake of TCN006 in the 200,000 ppm groups was 14,027.9 mg/kg bw/day for males and 20,507.0 mg/kg bw/day for females. At this concentration, palatability of water was likely affected, which led to a decrease in water consumption in both males and females compared to respective controls. This had no effect on the health of the animals. Although the rats were administered very high levels of (R)-3-Hydroxybutyrate glycerides, there were no signs of ketoacidosis.
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Água Potável , Glicerídeos , Humanos , Ratos , Masculino , Feminino , Animais , Ratos Wistar , Ácido 3-Hidroxibutírico , Peso Corporal , MamíferosRESUMO
PURPOSE: The purpose of the present study was to explore the utilization of cinnamon-coated gold nanoparticles (Cin-AuNPs) as CT/optical contrast-enhancement agents for detection of cancer cells. METHODS: Cin-AuNPs were synthesized by a "green" procedure, and the detailed characterization was performed by physico-chemical analysis. Cytotoxicity and cellular uptake studies were carried out in normal human fibroblast and cancerous (PC-3 and MCF-7) cells, respectively. The efficacy of detecting cancerous cells was monitored using a photoacoustic technique. In vivo biodistribution was studied after IV injection of Cin-AuNPs in mice, and also a CT phantom model was generated. RESULTS: Biocompatible Cin-AuNPs were synthesized with high purity. Significant uptake of these gold nanoparticles was observed in PC-3 and MCF-7 cells. Cin-AuNPs internalized in cancerous cells facilitated detectable photoacoustic signals. In vivo biodistribution in normal mice showed steady accumulation of gold nanoparticles in lungs and rapid clearance from blood. Quantitative analysis of CT values in phantom model revealed that the cinnamon-phytochemical-coated AuNPs have reasonable attenuation efficiency. CONCLUSIONS: The results indicate that these non-toxic Cin-AuNPs can serve as excellent CT/ photoacoustic contrast-enhancement agents and may provide a novel approach toward tumor detection through nanopharmaceuticals.
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Ouro/química , Nanopartículas Metálicas/química , Nanotecnologia/métodos , Neoplasias/diagnóstico , Intensificação de Imagem Radiográfica/métodos , Animais , Linhagem Celular Tumoral , Cinnamomum zeylanicum/química , Meios de Contraste/química , Fibroblastos , Humanos , Camundongos , Neoplasias/patologia , Imagens de Fantasmas , Processamento de Sinais Assistido por Computador , Distribuição TecidualRESUMO
PURPOSE: We report herein bombesin peptide conjugated water-soluble chitosan gallate as a template for rapid one-pot synthesis of gold nanoparticles (AuNPs) with capabilities to target receptors on prostate cancer cells. METHODS: Water-soluble chitosan (WCS), anchored with gallic acid (GA) and LyslLys3 (1,4,7,10-tetraazacyclo dodecane-1,4,7,10-tetraacetic acid) bombesin 1-14 (DBBN) peptide, provides a tumor targeting nanomedicine agent. WCS nanoplatforms provide attractive strategies with built-in capabilities to reduce gold (III) to gold nanoparticles with stabilizing and tumor-targeting capabilities. WCS-GA-DBBN encapsulation around gold nanoparticles affords optimum in vitro stability. RESULTS: The DBBN content in the WCS-GA-DBBN sample was ~27%w/w. The antioxidant activities of WCS-GA and WCS-GA-DBBN nanocolloids were enhanced by 12 times as compared to the nascent WCS. AuNPs with a desirable hydrodynamic diameter range of 40-60 nm have been efficiently synthesized using WCS-GA and WCS-GA-DBBN platforms. The AuNPs were stable over 4 days after preparation and ~3 days after subjecting to all relevant biological fluids. The AuNPs capped with WCS-GA-DBBN peptide exhibited superior cellular internalization into prostate tumor (PC-3) cells with evidence of receptor mediated endocytosis. CONCLUSION: The AuNPs capped with WCS-GA-DBBN exhibited selective affinity toward prostate cancer cells. AuNPs conjugated with WCS-GA-DBBN serve as a new generation of theranostic agents for treating various neoplastic diseases, thus opening-up new applications in oncology.
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Quitosana , Nanopartículas Metálicas , Neoplasias da Próstata , Bombesina , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Ouro , Humanos , Masculino , Peptídeos , Neoplasias da Próstata/tratamento farmacológico , ÁguaRESUMO
INTRODUCTION: Functionalization of water-soluble chitosan (WSCS) nanocolloids with, gold nanoparticles (AuNPs), and LyslLys3 (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-bombesin 1-14 (DOTA-BBN) peptide affords an innovative pathway to produce prostate tumor cell-specific nanomedicine agents with potential applications in molecular imaging and therapy. METHODS: The preparation involves the production and full characterization of water-soluble chitosan (WSCS), via gamma (γ) rays (80 kGy) irradiation, followed by DOTA-BBN conjugation for subsequent use as an effective template toward the synthesis of tumor cell-specific AuNPs-WSCS-DOTA-BBN. RESULTS: The WSCS-DOTA-BBN polymeric nanoparticles (86 ± 2.03 nm) served multiple roles as reducing and stabilizing agents in the overall template synthesis of tumor cell-targeted AuNPs. The AuNPs capped with WSCS and WSCS-DOTA-BBN exhibited average Au-core diameter of 17 ± 8 nm and 20 ± 7 nm with hydrodynamic diameters of 56 ± 1 and 67± 2 nm, respectively. The AuNPs-WSCS-DOTA-BBN showed optimum in vitro stability in biologically relevant solutions. The targeted AuNPs showed selective affinity toward GRP receptors overexpressed in prostate cancer cells (PC-3 and LNCaP). DISCUSSION: The AuNPs-WSCS-DOTA-BBN displayed cytotoxicity effects against PC-3 and LNCaP cancer cells, with concomitant safety toward the HAECs normal cells. The AuNPs-WSCS-DOTA-BBN showed synergistic targeting toward tumor cells with selective cytotoxicity of AuNPs towards PC-3 and LNCaP cells. Our investigations provide compelling evidence that AuNPs functionalized with WSCS-DOTA-BBN is an innovative nanomedicine approach for use in molecular imaging and therapy of GRP receptor-positive tumors. The template synthesis of AuNPs-WSCS-DOTA-BBN serves as an excellent non-radioactive surrogate for the development of the corresponding 198AuNPs theragnostic nanoradiopharmaceutical for use in cancer diagnosis and therapy.
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Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.
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Fatores Imunológicos/farmacologia , Nanopartículas Metálicas/química , Neoplasias da Próstata/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Xantonas/farmacologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ouro/química , Química Verde , Xenoenxertos , Humanos , Fatores Imunológicos/imunologia , Interleucina-12/genética , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/genética , Xantonas/químicaRESUMO
Biocompatibility studies and cancer therapeutic applications of nanoparticulate beta-emitting gold-198 (198Au; beta(max) = 0.96 MeV; half-life of 2.7 days) are described. Gum arabic glycoprotein (GA)-functionalized gold nanoparticles (AuNPs) possess optimum sizes (12-18 nm core diameter and 85 nm hydrodynamic diameter) to target individual tumor cells and penetrate through tumor vasculature and pores. We report the results of detailed in vivo therapeutic investigations demonstrating the high tumor affinity of GA-198AuNPs in severely compromised immunodeficient (SCID) mice bearing human prostate tumor xenografts. Intratumoral administration of a single dose of beta-emitting GA-198AuNPs (70 Gy) resulted in clinically significant tumor regression and effective control in the growth of prostate tumors over 30 days. Three weeks after administration of GA-198AuNPs, tumor volumes for the treated animals were 82% smaller as compared with tumor volume of control group. The treatment group showed only transitory weight loss in sharp contrast to the tumor-bearing control group, which underwent substantial weight loss. Pharmacokinetic studies have provided unequivocal evidence for the optimum retention of therapeutic payload of GA-198AuNPs within the tumor site throughout the treatment regimen with minimal or no leakage of radioactivity to various nontarget organs. The measurements of white and red blood cells, platelets, and lymphocytes within the treatment group resembled those of the normal SCID mice, thus providing further evidence on the therapeutic efficacy and concomitant in vivo tolerance and nontoxic features of GA-198AuNPs. FROM THE CLINICAL EDITOR: In this study, the biocompatibility and cancer therapeutic applications of glycoprotein (GA) functionalized gold nanoparticles containing b-emitting Au-198 are described in SCID mice bearing human prostate tumor xenografts. The findings of significant therapeutic efficacy, good in vivo tolerance and non-toxic features make these particles ideal candidates for future human applications.
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Portadores de Fármacos/química , Glicoproteínas/química , Radioisótopos de Ouro/química , Radioisótopos de Ouro/uso terapêutico , Goma Arábica/química , Nanopartículas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Feminino , Masculino , Camundongos , Camundongos SCID , Nanomedicina/métodos , Nanopartículas/química , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: The overarching objective of this investigation was to investigate the intervention of green nanotechnology to transform the ancient holistic Ayurvedic medicine scientifically credible through reproducible formulations and rigorous pre-clinical/clinical evaluations. METHODS: We provide, herein, full details: (i) on the discovery and full characterization of gold nanoparticles-based Nano Swarna Bhasma (henceforth referred to as NSB drug); (ii) In vitro anti-tumor properties of NSB drug in breast tumor cells; (iii) pre-clinical therapeutic efficacy studies of NSB drug in breast tumor bearing SCID mice through oral delivery protocols and (iv) first results of clinical translation, from mice to human breast cancer patients, through pilot human clinical trials, conducted according to the Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (abbreviated as AYUSH) regulatory guidelines of the Government of India in metastatic breast cancer patients. RESULTS: The preclinical in vitro and in vivo investigations, in breast tumor bearing mice, established unequivocally that the NSB Nano-Ayurvedic medicine-gold nanoparticles-based drug is highly effective in controlling the growth of breast tumors in a dose dependent fashion in vivo. These encouraging pre-clinical results prompted us to seek permission from the Indian Government's holistic medicine approval authority, AYUSH, for conducting clinical trials in human patients. Patients treated with the NSB drug capsules along with the "standard of care treatment" (Arm B) exhibited 100% clinical benefits when compared to patients in the treatment Arm A, thus indicating the tremendous clinical benefits of NSB drug in adjuvant therapy. CONCLUSION: We have succeeded in clinically translating, from mice to humans, in using proprietary combinations of gold nanoparticles and phytochemicals to develop the Nano-Ayurvedic drug: Nano Swarna Bhasma (NSB), through innovative green nanotechnology, for treating human metastatic breast cancer patients.
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Neoplasias da Mama/tratamento farmacológico , Ouro/farmacologia , Ayurveda/métodos , Nanopartículas Metálicas/química , Administração Oral , Adulto , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Ouro/química , Química Verde , Humanos , Índia , Mangifera/química , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/efeitos adversos , Nanopartículas Metálicas/uso terapêutico , Camundongos SCID , Pessoa de Meia-Idade , Nanotecnologia/métodos , Resultado do Tratamento , Xantonas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
INTRODUCTION: We report, herein, in vitro, and in vivo toxicity evaluation of silver nanoparticles stabilized with gum arabic protein (AgNP-GP) in Daphnia similis, Danio rerio embryos and in Sprague Dawley rats. PURPOSE: The objective of this investigation was to evaluate in vitro and in vivo toxicity of silver nanoparticles stabilized with gum arabic protein (AgNP-GP), in multispecies due to the recognition that toxicity evaluations beyond a single species reflect the environmental realism. In the present study, AgNP-GP was synthesized through the reduction of silver salt using the tri-alanine-phosphine peptide (commonly referred to as "Katti Peptide") and stabilized using gum arabic protein. METHODS: In vitro cytotoxicity tests were performed according to ISO 10993-5 protocols to assess cytotoxicity index (IC50) values. Acute ecotoxicity (EC50) studies were performed using Daphnia similis, according to the ABNT NBR 15088 protocols. In vivo toxicity also included evaluation of acute embryotoxicity using Danio rerio (zebrafish) embryos following the OECD No. 236 guidelines. We also used Sprague Dawley rats to assess the toxicity of AgNP-GP in doses from 2.5 to 10.0 mg kg-1 body weight. RESULTS: AgNP-GP nanoparticles were characterized through UV (405 nm), core size (20±5 nm through TEM), hydrodynamic size (70-80 nm), Zeta (ζ) potential (- 26 mV) using DLS and Powder X ray diffraction (PXRD) and EDS. PXRD showed pattern consistent with the Ag (1 1 1) peak. EC50 in Daphnia similis was 4.40 (3.59-5.40) µg L-1. In the zebrafish species, LC50 was 177 µg L-1. Oral administration of AgNP-GP in Sprague Dawley rats for a period of 28 days revealed no adverse effects in doses of up to 10.0 mg kg-1 b.w. in both male and female animals. CONCLUSION: The non-toxicity of AgNP-GP in rats offers a myriad of applications of AgNP-GP in health and hygiene for use as antibiotics, antimicrobial and antifungal agents.
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Daphnia/efeitos dos fármacos , Goma Arábica/química , Nanopartículas Metálicas/toxicidade , Prata/química , Peixe-Zebra/embriologia , Animais , Ecotoxicologia/métodos , Embrião não Mamífero/efeitos dos fármacos , Feminino , Dose Letal Mediana , Masculino , Nanopartículas Metálicas/química , Proteínas de Plantas/química , Ratos Sprague-Dawley , Especificidade da Espécie , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidadeRESUMO
This article describes several experiments performed to test our hypothesis that the agent used to coat/stabilize gold nanoparticles (AuNPs) will act to direct the AuNPs to specific tissues within the body and that changing the coating will change the target organ. Samples were also collected for pathological examination. Gum arabic- (GA) and maltose- (MALT) stabilized AuNPs were administered intravenously to juvenile swine, and blood, tissue, and urine samples were collected for gold analysis. Our results indicate that differences do exist between the two NP constructs tested, with 50% or greater of the total gold dose being found in the liver or lung for the GA- and MALT-stabilized AuNPs, respectively. These findings indicate that the functional unit used to coat/stabilize the AuNPs has an important role in determining the tissue distribution profile for individual AuNP constructs.
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Ouro/farmacocinética , Goma Arábica/química , Maltose/química , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Animais , Goma Arábica/administração & dosagem , Injeções Intravenosas , Maltose/administração & dosagem , Tamanho da Partícula , Suínos , Distribuição TecidualRESUMO
Background: As part of our continuing quest to enhance the efficacy of bioactive phytochemicals in cancer therapy, we report an innovative green nanotechnology approach toward the use of resveratrol for the production of biocompatible resveratrol-conjugated gold nanoparticles (Res-AuNPs). Our overarching aim is to exploit the inherent pro-apoptotic properties of gold nanoparticles (AuNPs) through synergistic anti-tumor characteristics of resveratrol, with the aim of developing a new class of green nanotechnology-based phytochemical-embedded AuNPs for applications in oncology. Method: Resveratrol was used to reduce Au3+ to Au0 for the synthesis of Res-AuNPs at room temperature and gum arabic (GA) was used to further encapsulate the nanoparticulate surface to increase the overall stability of the AuNPs. This comprehensive study involves the synthesis, full characterization and in vitro stability of Res-AuNPs in various biological media for their ultimate applications as anti-cancer agents against human breast (MDAMB-231), pancreatic (PANC-1) and prostate (PC-3) cancers. Results: This strategy to systematically increase the corona of resveratrol on AuNPs, in order to gain insights into the interrelationship of the phytochemical corona on the overall anti-tumor activities of Res-AuNPs, proved successful. The increased resveratrol corona on Res-AuNPs showed superior anti-cancer effects, attributed to an optimal cellular uptake after 24-hour incubation, while GA provided a protein matrix support for enhanced trans-resveratrol loading onto the surface of the AuNPs. Conclusion: The approach described in this study harnesses the benefits of nutraceuticals and nanoparticles toward the development of Res-AuNPs. We provide compelling evidence that the increased corona of resveratrol on AuNPs enhances the bioavailability of resveratrol so that therapeutically active species can be optimally available in vivo for applications in cancer therapy.
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Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Ouro/química , Nanopartículas Metálicas/química , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/patologia , Resveratrol/farmacologia , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Endocitose , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Nanopartículas Metálicas/ultraestrutura , Tamanho da Partícula , Polifenóis/química , Polifenóis/farmacologia , Resveratrol/química , Espectrofotometria Ultravioleta , Resultado do TratamentoRESUMO
The present study demonstrates an unprecedented green process for the production of gold nanoparticles by simple treatment of gold salts with soybean extracts. Reduction capabilities of antioxidant phytochemicals present in soybean and their ability to reduce gold salts chemically to nanoparticles with subsequent coating of proteins and a host of other phytochemicals present in soybean on the freshly generated gold nanoparticles are discussed. The new genre of green nanoparticles exhibit remarkable in vitro stability in various buffers including saline, histidine, HSA, and cysteine solutions. MTT assays reveal that the green gold nanoparticles are nontoxic and thus provide excellent opportunities for their applications in nanomedicine for molecular imaging and therapy. The overall strategy described herein for the generation of gold nanoparticles meets all 12 principles of green chemistry, as no "man-made" chemicals, other than the gold salts, are used in the green nanotechnological process.
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Materiais Biocompatíveis/química , Glycine max/química , Ouro/química , Nanopartículas Metálicas/química , Carboidratos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fenômenos Químicos , Físico-Química , Humanos , Isoflavonas/química , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Peso Molecular , Tamanho da Partícula , Proteínas de Plantas/química , EspectrofotometriaRESUMO
Gold nanoparticles (AuNPs) have exceptional stability against oxidation and therefore will play a significant role in the advancement of clinically useful diagnostic and therapeutic nanomedicines. Despite the huge potential for a new generation of AuNP-based nanomedicinal products, nontoxic AuNP constructs and formulations that can be readily administered site-specifically through the intravenous mode, for diagnostic imaging by computed tomography (CT) or for therapy via various modalities, are still rare. Herein, we report results encompassing: 1) the synthesis and stabilization of AuNPs within the nontoxic phytochemical gum-arabic matrix (GA-AuNPs); 2) detailed in vitro analysis and in vivo pharmacokinetics studies of GA-AuNPs in pigs to gain insight into the organ-specific localization of this new generation of AuNP vector, and 3) X-ray CT contrast measurements of GA-AuNP vectors for potential utility in molecular imaging. Our results demonstrate that naturally occurring GA can be used as a nontoxic phytochemical construct in the production of readily administrable biocompatible AuNPs for diagnostic and therapeutic applications in nanomedicine.
Assuntos
Ouro/química , Ouro/farmacocinética , Goma Arábica/química , Goma Arábica/farmacocinética , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanotecnologia/métodos , Animais , Meios de Contraste , Cristalização/métodos , Excipientes/química , Cinética , Substâncias Macromoleculares/química , Teste de Materiais , Taxa de Depuração Metabólica , Conformação Molecular , Tamanho da Partícula , Propriedades de Superfície , Suínos , Distribuição Tecidual , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: In our previous work, we have extensively evaluated the physiochemical characteristics of Gum Arabic-encapsulated gold nanoparticles (GA-AuNPs; 15-18nm) and reported their effectiveness in stopping the tumor initiation via inhibiting the pre-neoplastic lesions in liver. OBJECTIVE: The rationale of this study is to detect the efficiency of using GA-AuNPs in photothermal application as a non-invasive technique against lung tumor. We investigated the cytotoxicity of GA-AuNPs on A549 cells, and then studied their apoptotic, anti-inflammatory, lipid peroxidation and anti-neovascular effect in in vivo model using a chemically-induced lung cancer in mice. The histopathological changes due to GA-AuNPs were investigated. RESULTS: In the presence of laser irradiation, GA-AuNPs had a considerable cytotoxicity against A549 cells. The treatment of lung tumor-bearing mice with GA-AuNPs followed by laser exposure enhanced the apoptotic pathway and this was obvious from the histopathological investigations and the elevations in cytochrome-c, death receptor 5 and the subsequent upregulation of caspase-3, we also reported a significant reduction in the levels of the inflammatory mediator TNF-α and the angiogenesis inducer VEGF. An induction of lipid peroxidation was also reported upon treatment with either GA or GA-AuNPs. CONCLUSION: GA-AuNPs showed no cytotoxicity in the absence of light, however the combination of GA-AuNPs with laser induced cell death in lung tumor tissues with a reduction in the inflammation and angiogenesis together with an elevation in lipid peroxidation, suggesting the potential use of these functionalized nanoparticles as a promising photothermal non-invasive treatment modality.
Assuntos
Ouro/farmacologia , Goma Arábica/química , Neoplasias Pulmonares/terapia , Nanopartículas Metálicas/química , Fototerapia/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ouro/química , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
This study validates the utility of Gum Arabic-conjugated gold nanoparticles (GA-AuNPs) and laser to induce photothermal inhibition of hepatocarcinogenesis, via employing a diethylnitrosamine (DEN)-mediated hepatocellular carcinoma model. This work included both of in vitro and in vivo studies; to investigate the GA-AuNPs cytotoxicity and phototoxicity in hepatic cell line; to delineate the GA-AuNPs therapeutic efficiency in DEN-induced preneoplastic lesions (PNLs) in the liver of Balb-C mice. The therapeutic effects of GA-AuNPs on the mediators of apoptosis, inflammation, and tumor initiation, as well as the histopathological changes in preneoplastic liver have been investigated. Our results infer that GA-AuNPs in combination with laser irradiation led to a significant reduction in the cell viability and in histone deacetylase activity in hepatocarcinoma HepG2 cells. In chemically-induced PNLs mice model our results have demonstrated that GA-AuNPs, with or without laser irradiation, induced cancer cell apoptosis through the activation of death receptors DR5 and caspase-3 and inhibited both of the PNLs incidence and the initiation marker (placental glutathione S-transferase; GST-P). The laser-stimulated GA-AuNPs significantly reduced the tumor necrosis factor-α levels. In summary, GA-AuNPs with laser treatment inhibited liver PNLs via the induction of the extrinsic apoptosis pathway and the inhibition of inflammation.
Assuntos
Ouro/química , Goma Arábica/química , Goma Arábica/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas Metálicas/química , Fototerapia/métodos , Lesões Pré-Cancerosas/terapia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Transformação Celular Neoplásica , Dietilnitrosamina/efeitos adversos , Glutationa S-Transferase pi/metabolismo , Células Hep G2 , Histona Acetiltransferases/metabolismo , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Necrose , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A novel hydrophilic gold compound, tetrakis((trishydroxymethyl)phosphine)gold(I) chloride 1, has been investigated for its antitumor properties. In vitro studies demonstrate that 1 is active against HCT-15, AGS, PC-3, and LNCaP tumor cells. Cell cycle analysis of the HCT-15 cells by flow cytometry revealed elongation of the G1 phase of the cell cycle leading to growth inhibition. Administration of 1 to Balb/C mice inoculated with syngenic meth/A cells demonstrated statistically significant dose-dependent survival time.
Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Fosfinas/farmacologia , Animais , Antineoplásicos/síntese química , Ciclo Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Citometria de Fluxo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neoplasias Experimentais/mortalidade , Compostos Organoáuricos , Compostos Organometálicos/química , Fosfinas/química , Células Tumorais CultivadasRESUMO
The development of new treatment modalities that offer clinicians the ability to reduce sizes of tumor prior to surgical resection or to achieve complete ablation without surgery would be a significant medical breakthrough in the overall care and treatment of prostate cancer patients. The goal of our investigation is aimed at validating the hypothesis that Gum Arabic-functionalized radioactive gold nanoparticles (GA-(198) AuNP) have high affinity toward tumor vasculature. We hypothesized further that intratumoral delivery of the GA-(198) AuNP agent within prostate tumor will allow optimal therapeutic payload that will significantly or completely ablate tumor without side effects, in patients with hormone refractory prostate cancer. In order to evaluate the therapeutic efficacy of this new nanoceutical, GA-(198) AuNP was produced by stabilization of radioactive gold nanoparticles ((198) Au) with the FDA-approved glycoprotein, GA. This review will describe basic and clinical translation studies toward realization of the therapeutic potential and myriad of clinical applications of GA-(198) AuNP agent in treating prostate and various solid tumors in human cancer patients.