1,720,967 research outputs found
Controlled Delivery of Nitric Oxide Using Stable and Stimuli-Responsive S-nitrosothiols
No full textNitric oxide (NO) is a short-lived, endogenously produced gas which plays multiple roles in mammalian physiology. A broad range of NO donors has emerged as potential therapeutics in different pathological processes including cardiovascular and respiratory disorders, wound healing, the immune response to infection and cancer. However, limited NO payloads, too rapid NO release, and the lack of organ or tissue specificity have limited the clinical utility of currently available NO donors.
Herein, three main strategies were used to make stable and stimuli-responsive NO donors using S-nitrosothiols (SNTs). First, we have developed photoactive nanoparticles (NPs) by encapsulation of a hydrophobic and stable SNT, tert-dodecane s-nitrosothiol (tDodSNO), into polystyrene maleic acid (SMA) to make nano-sized SMA-tDodSNO particles. Encapsulation of tDodSNO physically protects it from metabolic breakdown as well as trans-nitrosation reactions with proteins and thiols, thereby inhibits unspecific NO release. In the absence of photo-irradiation, NPs had a half-life (t1/2) of approximately 104 h, while photoactivation (cold light with the intensity of 2700 W/m2) decreased this to just 3.5 min. Second, a stable and tuneable NO-releasing compound was synthesized which contains hydrophobic and sterically hindered SNT as well as a carboxylate group far from the SNT group. The compound showed sustained NO release in the dark (t1/2= 300 h) while upon photoactivation is degraded within a few mins (t1/2= 5.5 min). Third, by combining these two approaches and attachment of the synthesized SNT to SMA to produce a novel NO-releasing polymer (SMASNO). The unactivated polymer has a NO release half-life of approximately 392 h, and photoactivation decreased this to 23 min. Photoactivation of SMA-tDodSNO resulted in an 18-fold shift in the EC50 of rat’s aortic ring vasorelaxation and also induced localized hyperpermeability in rats mesenteric bed with microscopic analysis indicating that the SMA-tDodSNO increased tissue uptake through a combination of photoactivation induced vasodilation and extravasation. SMA-tDodSNO showed significant cytotoxicity in 4T1 cell line and when combined with doxorubicin (Dox) it synergistically arrested cell proliferation and induced apoptosis. Due to NO release, it enhanced the endocytosis of a Dox-loaded NP (SMA-Dox) and increased the permeability of the endosomal membrane, hence facilitated the escape of the NPs, and reduced Dox efflux from the cells.
Similarly, photoactivation of SMASNO shifted the EC50 of the aortic ring to 12-fold lower concentrations. The polymer could self-assemble to form containing the hydrophobic fluorescent dye Nile Red (NR) as a traceable drug analog to form NRNPs. The NR release from the particles was increased in either the presence of high levels of glutathione or in response to photoactivation, indicating that the NP could release its cargo in response to specific stimuli. When NRNPs were perfused into a rat mesenteric bed, then a region of the bed irradiated by cold light was significantly higher than other parts of the bed.
In conclusion, stable and stimuli-responsive NO-releasing compounds were made using hydrophobic and bulky SNTs covalently attached or self-assembled with hydrophilic moieties. We report that the stimuli-responsive NO-releasing NPs can be used to overcome some of the barriers in front of efficient chemotherapy, as they can enhance blood supply, vessel permeability in tumor tissues, endocytosis and endosomal escape of NPs, and inhibit drug resistance
Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery
No full textABSTRACT
The oral route is the preferred mode of drug administration due to its non-invasive nature, economical benefits, and the potential to improve patients’ quality of life. Oral administration of anticancer agents can be tailored to maintain plasma concentrations above therapeutic level and ensure prolonged and effective exposure of cancer cells to the chemotherapeutic agent. However in cancer therapy, most drugs are administered intravenously due to their low oral bioavailability and gastrointestinal (GI) toxicity. The use of a nanocarrier system for oral delivery of anticancer drugs can eliminate the toxicity to the GI tract, improve the bioavailability and take advantage of the wide fenestrations of tumour vasculature to accumulate in the tumour tissue. Despite a plethora of research being dedicated to the development of nanosized formulations, there is still no oral anticancer nanomedicine in clinical use. This thesis evaluates the potential of styrene maleic acid (SMA) micelles as a nanocarrier system for oral anticancer drug delivery.
SMA micelles encapsulating epirubicin (as a fluorescent model of anticancer drug) or a fluorescent dye, DiI (1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) or paclitaxel (PTX) were synthesised and characterised. All the SMA micelles had a good recovery (80 – 97%). Their sizes were > 7 nm enabling them to escape renal clearance and prolong their circulatory half-lives. The SMA micelles had a neutral charge which would aid in reducing opsonisation in the circulation. The SMA micelles were more stable at physiological pH and intestinal pH as compared to gastric pH. Nevertheless, all the SMA micelles showed less than 15% release in gastric environment in the initial 2 h, which is the gastric transit time. Furthermore, on comparing the release rate of 7.5 and 18% loaded SMA-Epi micelles, it was observed that lower loaded micelles showed faster release of the drug. However, both the micelles showed less than 15% release in the initial 8 h.
The SMA-Epi micelles were efficiently transported across the intestinal epithelium using in vitro and ex vivo model, while maintaining the tissue integrity. SMA micelles showed uptake by clathrin-dependent endocytosis and micropinocytosis through the cells of the intestinal epithelium. The in vivo biodistribution of SMA micelles was evaluated using DiI. Oral administration of SMA-DiI resulted in 2-fold higher accumulation in liver and spleen, and 15-fold higher accumulation in the tumour as compared to the free DiI. Furthermore, it was observed that the SMA micelles show dual uptake through enterocytes and M cells in an in vivo tumour model, which was confirmed by visualising the accumulation of SMA micelles in the Peyer`s patches.
Furthermore, the antitumour efficacy of the orally administered SMA micelles encapsulating PTX was evaluated in the last section. The maximum tolerated dose (MTD) of SMA-PTX through oral administration was higher than the commercially available PTX formulation (PTX, Ebewe), for both single (120 vs 60 mg/kg) and repeated doses (60 vs 30 mg/kg). Thus the SMA-PTX could be administered at higher doses to achieve better therapeutic efficacy. In a CT-26 (Balb/c colon cancer cells) orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 and 60 mg/kg reduced tumour weight by 54 and 69% respectively, as compared to the control group, while no significant reduction in tumour weight was observed with 30 mg/kg of PTX (Ebewe). This therapeutic effect is attributed to the enhanced tumour accumulation of the SMA micellar system, through the systemic circulation as well as paracellular transport through the epithelium lining the colon tumours. However, oral administration of SMA-PTX did not show significant reduction in tumour size in a MDA-MB-231 breast cancer xenograft model, as compared to the control, at a dose of 30 mg/kg. In both the tumour models, oral administration of SMA-PTX micelles did not show any liver or kidney toxicity. In conclusion, SMA micelles could provide an effective strategy for safe oral administration of PTX in cancer therapy for GI tumours. Nevertheless, further optimisation of dose and dosing schedule would be needed to ascertain the efficacy of oral administration of SMA-PTX in breast cancer xenograft model
Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery
No full textABSTRACT
The oral route is the preferred mode of drug administration due to its non-invasive nature, economical benefits, and the potential to improve patients’ quality of life. Oral administration of anticancer agents can be tailored to maintain plasma concentrations above therapeutic level and ensure prolonged and effective exposure of cancer cells to the chemotherapeutic agent. However in cancer therapy, most drugs are administered intravenously due to their low oral bioavailability and gastrointestinal (GI) toxicity. The use of a nanocarrier system for oral delivery of anticancer drugs can eliminate the toxicity to the GI tract, improve the bioavailability and take advantage of the wide fenestrations of tumour vasculature to accumulate in the tumour tissue. Despite a plethora of research being dedicated to the development of nanosized formulations, there is still no oral anticancer nanomedicine in clinical use. This thesis evaluates the potential of styrene maleic acid (SMA) micelles as a nanocarrier system for oral anticancer drug delivery.
SMA micelles encapsulating epirubicin (as a fluorescent model of anticancer drug) or a fluorescent dye, DiI (1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) or paclitaxel (PTX) were synthesised and characterised. All the SMA micelles had a good recovery (80 – 97%). Their sizes were > 7 nm enabling them to escape renal clearance and prolong their circulatory half-lives. The SMA micelles had a neutral charge which would aid in reducing opsonisation in the circulation. The SMA micelles were more stable at physiological pH and intestinal pH as compared to gastric pH. Nevertheless, all the SMA micelles showed less than 15% release in gastric environment in the initial 2 h, which is the gastric transit time. Furthermore, on comparing the release rate of 7.5 and 18% loaded SMA-Epi micelles, it was observed that lower loaded micelles showed faster release of the drug. However, both the micelles showed less than 15% release in the initial 8 h.
The SMA-Epi micelles were efficiently transported across the intestinal epithelium using in vitro and ex vivo model, while maintaining the tissue integrity. SMA micelles showed uptake by clathrin-dependent endocytosis and micropinocytosis through the cells of the intestinal epithelium. The in vivo biodistribution of SMA micelles was evaluated using DiI. Oral administration of SMA-DiI resulted in 2-fold higher accumulation in liver and spleen, and 15-fold higher accumulation in the tumour as compared to the free DiI. Furthermore, it was observed that the SMA micelles show dual uptake through enterocytes and M cells in an in vivo tumour model, which was confirmed by visualising the accumulation of SMA micelles in the Peyer`s patches.
Furthermore, the antitumour efficacy of the orally administered SMA micelles encapsulating PTX was evaluated in the last section. The maximum tolerated dose (MTD) of SMA-PTX through oral administration was higher than the commercially available PTX formulation (PTX, Ebewe), for both single (120 vs 60 mg/kg) and repeated doses (60 vs 30 mg/kg). Thus the SMA-PTX could be administered at higher doses to achieve better therapeutic efficacy. In a CT-26 (Balb/c colon cancer cells) orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 and 60 mg/kg reduced tumour weight by 54 and 69% respectively, as compared to the control group, while no significant reduction in tumour weight was observed with 30 mg/kg of PTX (Ebewe). This therapeutic effect is attributed to the enhanced tumour accumulation of the SMA micellar system, through the systemic circulation as well as paracellular transport through the epithelium lining the colon tumours. However, oral administration of SMA-PTX did not show significant reduction in tumour size in a MDA-MB-231 breast cancer xenograft model, as compared to the control, at a dose of 30 mg/kg. In both the tumour models, oral administration of SMA-PTX micelles did not show any liver or kidney toxicity. In conclusion, SMA micelles could provide an effective strategy for safe oral administration of PTX in cancer therapy for GI tumours. Nevertheless, further optimisation of dose and dosing schedule would be needed to ascertain the efficacy of oral administration of SMA-PTX in breast cancer xenograft model
The use of combination tyrosine kinase inhibitors for the treatment of glioblastoma multiforme
Get PDFGlioblastoma is the most common primary brain tumor which has a median survival of only 14.6 months. The central nervous system localization, heterogeneity of the cells and resistance to treatment constitute a significant challenge to establishing an efficient and durable therapy. Glioblastoma lesions contain a dense network of defective blood vessels which are permeable to high molecular weight constructs such as nanocarriers. Furthermore, glioblastoma lesions are known to depend upon several tyrosine kinases in order to facilitate their development, progression, invasion and treatment resistance.
As a consequence, we assessed the cytotoxicity of multiple tyrosine kinase inhibitors (TKIs), singularly or in combination, against a panel of glioblastoma cell lines in vitro. The most promising combination of crizotinib, an inhibitor of Met and ROS1, and dasatinib, an inhibitor of SRC and focal adhesion kinase (FAK), were pursued as the lead compounds. In addition, these TKIs were encapsulated into polystyrene co-maleic acid micelles to improve their pharmacokinetic profiles in vivo by selective accumulation in tissues with fenestrated vasculature. The micelles were characterized based on their loading, charge, size, solubility and release rate. Both formulations were assessed for their ability to alter protein expression profiles, induce cell death and reduce proliferation. The ability of the treatments to prevent migration, invasion and angiogenesis in a panel of glioblastoma cell lines was also assessed.
The micelles had favorable physicochemical characteristics, with a size sufficient to promote a prolonged plasma half-life, a near neutral charge to prevent opsonization and a steady release rate. The expression and phosphorylation of the target kinases Met, ROS1, SRC, and FAK were consistently reduced by the combination treatment. The combination treatment also reduced the expression of EGFR despite neither TKI targeting this receptor. The inhibition of these targets and subsequent suppression of downstream AKT activity induced apoptotic cell death in glioblastoma cells. The cell death following removal of the drug after a 72 h treatment period, defined as washout, was assessed to determine the ability of the cells to escape from treatment-induced cell death. Following washout, the apoptosis was maintained for 72 h following the removal of the drugs in the free but not the micellar formulations. The induction of cell death correlated with the induction of polyploidy in the free but not micellar formulations. This polyploidy was not causative of cell death but was associated with genetic instability. Both free and micellar formulations showed effective prevention of invasion, migration and angiogenesis in vitro.
This study demonstrated the efficacy of the combination of crizotinib and dasatinib in a panel of glioblastoma cell lines. This combination strongly induced apoptotic cell death. Furthermore, the combination also effectively combated several treatment resistance pathways such as invasion and vascular mimicry, potentially augmenting the efficacy of the current therapies. The micellar formulations show comparable efficacy to the free formulations but also provide the potential for the improvement of in vivo pharmacokinetic parameters. In conclusion, the combination of crizotinib and dasatinib shows significant promise in vitro and warrants further investigation in vivo for the treatment of glioblastoma
Controlled Delivery of Nitric Oxide Using Stable and Stimuli-Responsive S-nitrosothiols
No full textNitric oxide (NO) is a short-lived, endogenously produced gas which plays multiple roles in mammalian physiology. A broad range of NO donors has emerged as potential therapeutics in different pathological processes including cardiovascular and respiratory disorders, wound healing, the immune response to infection and cancer. However, limited NO payloads, too rapid NO release, and the lack of organ or tissue specificity have limited the clinical utility of currently available NO donors.
Herein, three main strategies were used to make stable and stimuli-responsive NO donors using S-nitrosothiols (SNTs). First, we have developed photoactive nanoparticles (NPs) by encapsulation of a hydrophobic and stable SNT, tert-dodecane s-nitrosothiol (tDodSNO), into polystyrene maleic acid (SMA) to make nano-sized SMA-tDodSNO particles. Encapsulation of tDodSNO physically protects it from metabolic breakdown as well as trans-nitrosation reactions with proteins and thiols, thereby inhibits unspecific NO release. In the absence of photo-irradiation, NPs had a half-life (t1/2) of approximately 104 h, while photoactivation (cold light with the intensity of 2700 W/m2) decreased this to just 3.5 min. Second, a stable and tuneable NO-releasing compound was synthesized which contains hydrophobic and sterically hindered SNT as well as a carboxylate group far from the SNT group. The compound showed sustained NO release in the dark (t1/2= 300 h) while upon photoactivation is degraded within a few mins (t1/2= 5.5 min). Third, by combining these two approaches and attachment of the synthesized SNT to SMA to produce a novel NO-releasing polymer (SMASNO). The unactivated polymer has a NO release half-life of approximately 392 h, and photoactivation decreased this to 23 min. Photoactivation of SMA-tDodSNO resulted in an 18-fold shift in the EC50 of rat’s aortic ring vasorelaxation and also induced localized hyperpermeability in rats mesenteric bed with microscopic analysis indicating that the SMA-tDodSNO increased tissue uptake through a combination of photoactivation induced vasodilation and extravasation. SMA-tDodSNO showed significant cytotoxicity in 4T1 cell line and when combined with doxorubicin (Dox) it synergistically arrested cell proliferation and induced apoptosis. Due to NO release, it enhanced the endocytosis of a Dox-loaded NP (SMA-Dox) and increased the permeability of the endosomal membrane, hence facilitated the escape of the NPs, and reduced Dox efflux from the cells.
Similarly, photoactivation of SMASNO shifted the EC50 of the aortic ring to 12-fold lower concentrations. The polymer could self-assemble to form containing the hydrophobic fluorescent dye Nile Red (NR) as a traceable drug analog to form NRNPs. The NR release from the particles was increased in either the presence of high levels of glutathione or in response to photoactivation, indicating that the NP could release its cargo in response to specific stimuli. When NRNPs were perfused into a rat mesenteric bed, then a region of the bed irradiated by cold light was significantly higher than other parts of the bed.
In conclusion, stable and stimuli-responsive NO-releasing compounds were made using hydrophobic and bulky SNTs covalently attached or self-assembled with hydrophilic moieties. We report that the stimuli-responsive NO-releasing NPs can be used to overcome some of the barriers in front of efficient chemotherapy, as they can enhance blood supply, vessel permeability in tumor tissues, endocytosis and endosomal escape of NPs, and inhibit drug resistance
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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