Gareth Kilian - Academia.edu (original) (raw)

Papers by Gareth Kilian

Research paper thumbnail of The Properties, Formation, and Biological Activity of 2,5-Diketopiperazines

Elsevier eBooks, 2010

... further investigation of their clinical potential essential. Related research. Biological act... more ... further investigation of their clinical potential essential. Related research. Biological activity of selected tyrosine-containing 2,5-diketopiperazines. G Kilian, H Jamie, SCA Brauns, K Dyason, PJ Milne in Die Pharmazie (2005). ...

Research paper thumbnail of Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala)

PubMed, Mar 1, 2013

Cyclic dipeptides have been well characterized for their biological activity, including antimicro... more Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

Research paper thumbnail of The effects of creatine on the retrogradely perfused isolated rat heart

Journal of Pharmacy and Pharmacology, 2002

Although the role of creatine in muscle metabolism is well understood, there is still uncertainty... more Although the role of creatine in muscle metabolism is well understood, there is still uncertainty as to its effects at supplemented levels. With this in mind, this study was designed to investigate the direct effects of commercially available creatine on the isolated rat heart, retrogradely perfused and infused with varying concentrations of creatine (1.25, 2.5, 5 and 10 mM) to determine its effects on heart rate, coronary ow and ventricular pressure. Furthermore, tissue from these hearts was used to investigate the cardiotoxic potential of supplemented levels of creatine. Results indicate that creatine directly improves the functioning of the heart under normal conditions with respect to heart rate and ventricular pressure, but may be detrimental to the functioning of energy-deprived hearts. It also showed no cardiotoxic properties since it increased the baseline levels of adenosine triphosphate (ATP) and decreased the levels of isocitrate dehydrogenase (ICD), indicating a decrease in cellular death compared with nonsupplemented control hearts.

Research paper thumbnail of Hepatotoxicity of the isomers of cyclo(Trp-Pro)

PubMed, Sep 1, 2002

The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage ... more The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage in various pharmacological fields, had not been assessed. Further studies on the isomers of this cyclic dipeptide (cyclo(L-Trp-L-Pro), cyclo-(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro)) revealed further biological activities. The assessment of hepatotoxicity of these isomers was thus warranted. In vitro screens were performed on primary isolated rat hepatocytes, the Chang liver and N-2-alpha cell lines. In vivo screening involved the assessment of serum levels of lactate dehydrogenase, aspartate transaminase, ATP, Ca2+ and albumin after intraperitoneal injection over a 1 and 5 day period in the rat model. Liver samples were also obtained for the assessment of lipid peroxidation. It was found that only cyclo(D-Trp-L-Pro) was hepato-specific in its action, while the other isomers were not. The greatest effect on any biochemical or physiological parameter was noted after 5 days. LDH secretion was greatly increased in the presence of cyclo(L-Trp-L-Pro) and cyclo-(L-Trp-D-Pro) (p < 0.05). Significantly increased levels of lipid peroxidation were observed in all the isomer-treated samples (p < 0.05), while Ca2+ concentrations were decreased at day 5. Decreased protein synthesis was noted in the presence of all the isomers at day 1. These results indicate the potential harm involved in the administration of the isomers, which may limit their potential usage in the treatment of various diseases.

Research paper thumbnail of The effect of the isomers of cyclo(Trp-Pro) on heart and ion-channel activity

Journal of Pharmacy and Pharmacology, Dec 1, 2002

Research paper thumbnail of Optimization of selected liposome-encapsulated diketopiperazines

Journal of Drug Delivery Science and Technology, 2014

Response surface methodology (RSM) is an effective way to optimize various processes and formulat... more Response surface methodology (RSM) is an effective way to optimize various processes and formulations were investigators are able to determine how variables influence the formulation by assessing interaction effects in order to obtain an optimum formulation. Cyclic dipeptides have been shown to inhibit tumor cells but problems with their physicochemical characteristics have limited further development of these compounds clinically. The aim was to optimize a liposome-based drug delivery system incorporating cyclo(His-Gly) and cyclo(His-Ala) using response surface methodology. Liposomes, containing varying compositions of phosphatidylcholine, cholesterol, stearylamine, vitamin E and PEG2000-phosphatidylethanolamine were prepared according to the thin film hydration and extrusion method. Drugs were passively encapsulated and separated from free drug using Sephadex G50 columns. RSM, utilizing a central composite rotatable design (CCRD) was used to assess the influence of selected variables on encapsulation, uptake, membrane leakage, polydispersity and zeta potential. A quadratic model was used to fit data for all responses. The most significant interaction was between cholesterol and stearylamine content with cellular uptake, indicating that these parameters cannot be altered independently of each other. Optimization of the formulation yielded stable liposomes with an average encapsulation of 0.123 mg drug/mg lipid.

Research paper thumbnail of Biological activity of selected tyrosine-containing 2,5-diketopiperazines

PubMed, Apr 1, 2005

The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with ... more The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with respect to their biological activity. Investigations using the whole-cell patch-clamp technique testing the effects of 100 microM cyclic dipeptide on ion channels, revealed reversible voltage-dependant blockade for cTT, while cPT exhibited irreversible time-dependant blockade of L-type calcium channels. The isolated retrogradely-perfused rat heart was used to determine the effects of 100 microM of either cTT or cPT on heart rate (HR), coronary flow rate (CFR), left ventricular systolic pressure (LVSP) and cardiac conduction speed. Results indicated opposing effects for the two compounds, where cTT increased HR and CF while cPT decreased HR, CF, LVSP as well as conduction speed. Other biological investigations included opioid binding and anti-neoplastic assays. Competitive binding curves, using tritiated DAMGO, revealed significant binding to micro-opioid receptors with IC50 values for cTT and cPT being 0.82 microM and 69.7 microM respectively. Anti-neoplastic activity was tested using three cultured cell lines: HT-29, MCF-7 and HeLa which were exposed to 2.5 mM cyclic dipeptide or 0.1 mM melphalan as a positive control. While cTT showed little activity against these lines, cPT resulted in as much as a 75.6% growth inhibition of MCF-7 cells, while also being active against HeLa (73.4% inhibition) and HT-29 (60.6%). The results indicate potential biological activity, showing a need for more investigation into tyrosine containing cyclic dipeptides and their analogues as potential bioactive compounds.

Research paper thumbnail of The development of folate-functionalised palladium nanoparticles for folate receptor targeting in breast cancer cells

Nanotechnology

Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A no... more Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A non-toxic concentration of folate-conjugated palladium-based nanoparticles was used to target the overexpressed folate receptor on breast cancer cells. The folate-conjugated nanoparticles were tailored to accumulate selectively in cancer cells relative to normal cells via the folate receptor. The MDA-MB-231, MDA-MB-468, MCF-7 breast cancer cell lines, and MCF-10A normal cell lines were used in the study. Qualitative and quantitative analysis of nanoparticle cellular uptake and accumulation was conducted using transmission electron microscopy and inductively coupled plasma-optical emission spectroscopy. The findings proved that folate-conjugated palladium nanoparticles successfully and preferentially accumulated in breast cancer cells. We conclude that folate-conjugated palladium nanoparticles can be potentially used to target breast cancer cells for radiopharmaceutical applications.

Research paper thumbnail of Learning and teaching in the time of COVID-19

Research paper thumbnail of The Introduction of Process Analytical Technology, Using Near Infrared Analysis, to a Pharmaceutical Blending Process

This study investigates the use of a laboratory scale blender fitted with a near infrared probe t... more This study investigates the use of a laboratory scale blender fitted with a near infrared probe to monitor lubricant uniformity in a granule blend. A software method was developed to monitor the change in absorbance at significant wavelengths for the granule and lubricant (magnesium stearate) as the blend proceeded in real-time. The standard deviation of the absorbance was plotted as a function of time to monitor the change in the blend. With near infrared spectra, when a process is complete, the spectra will not change, therefore the standard deviation will be small [6]. To verify this, the blend was sampled using a standard sampling method and analyzed with an atomic absorption method for magnesium stearate to ascertain the distribution in the blend. Blends sampled at the predetermined time intervals were well blended when the standard deviation of the absorbance was low and poorly blended when the standard deviation of the absorbance was high, thus verifying the near infrared pre...

Research paper thumbnail of Academia 2.0

Some days I have to stop myself when I’m prompted to say, “When I was a student …” in response to... more Some days I have to stop myself when I’m prompted to say, “When I was a student …” in response to a student request that would have seemed completely out of line 20 years ago. As academics, we find ourselves in an ever changing environment where the demand for flexibility almost requires that each of us take regular yoga classes.

Research paper thumbnail of Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala)

Pharmazie

Cyclic dipeptides have been well characterized for their biological activity, including antimicro... more Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

Research paper thumbnail of Antimicrobial activity of liposome encapsulated cyclo(L-tyrosyl-L-prolyl)

Pharmazie

Various studies have shown the potentially beneficial biological activities of cyclic dipeptides ... more Various studies have shown the potentially beneficial biological activities of cyclic dipeptides and in particular, cyclo(L-tyrosyl-L-prolyl) (cyclo(Tyr-Pro)) has shown fair antibacterial activity in vitro. This study aimed to determine if liposome encapsulation would have any significant effects on the antibacterial activity of this compound. The thin-film hydration method with extrusion was used to produce small unilamellar vesicles containing cyclo(Tyr-Pro) that were shown to have an average encapsulation of 9.4% with a mean particle size of 160.4 nm. Minimum inhibitory concentrations tested against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Bacillus subtillis were shown to be lower in liposome encapsulated cyclo(Tyr-Pro) than for the free form, while no antimicrobial activity was noted for either encapsulated nor non-encapsulated drug against the fungus Candida albicans or two methicillin-resistant strains of Staphylococcus aureus (MRSA). A positive control of liposome encapsulated amoxicillin was shown to be extremely active against both MRSA strains. The results confirm that liposome encapsulation has the potential to enhance activity as well as to overcome bacterial resistance towards current antibacterial agents.

Research paper thumbnail of The medicinal chemistry of aromatic cyclic dipeptides : cyclo(Tyr-Tyr) and cyclo(Phe-Tyr) /

Research paper thumbnail of Biological activity of tyrosine-containing 2,5-diketopiperazines

Research paper thumbnail of The synthesis and anticancer activity of selected diketopiperazines

Research paper thumbnail of The biological activity of the histidine-containing diketopiperazines cyclo(His-Ala) and cyclo(His-Gly)

Peptides, 2006

Two cyclic dipeptides, cyclo(His-Ala) and cyclo(His-Gly,) were synthesized from their linear coun... more Two cyclic dipeptides, cyclo(His-Ala) and cyclo(His-Gly,) were synthesized from their linear counterparts and their structures elucidated using standard elucidation techniques. Molecular modeling and predictive NMR results indicated that the majority of energetically favourable conformers adopted a boat conformation with respect to the diketopiperazine ring. Cyclo(His-Ala), at concentrations of 100 mM inhibited the growth, in vitro, of various cancer cell lines, including HT-29, MCF-7 and HeLa carcinoma cells while cyclo(His-Gly) inhibited the growth of MCF-7 cells. While the antibacterial potential of these two compounds was limited, both cyclic dipeptides significantly inhibited the growth of C. albicans. Both compounds at a concentration of 100 mM resulted in a decrease in heart rate, coronary flow rate and left ventricular systolic pressure in the isolated rat heart. Inhibition of thrombin, amounting to a 63.3% and 36.7% reduction in the rate of fibrin formation, was noted for cyclo(His-Ala) and cyclo(His-Gly), respectively. While cyclo(His-Ala) showed no notable effects on platelet aggregation, cyclo(His-Gly) significantly inhibited both pathways tested with greatest effects on thrombin-induced platelet aggregation, yielding an IC 50 of 0.0662 mM (R 2 = 0.989). The results of the anticancer and hematological studies indicate that histidine-containing diketopiperazines have potential as a novel group of cytotoxic agents with antithrombotic effects.

Research paper thumbnail of The effect of the isomers of cyclo(Trp-Pro) on heart and ion-channel activity

Journal of Pharmacy and Pharmacology, 2002

Cyclo(l-Trp-l-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. Th... more Cyclo(l-Trp-l-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. The aim of the study was to determine the effects of the isomers of cyclo(Trp-Pro) - cyclo(l-Trp-l-Pro), cyclo(l-Trp-d-Pro), cyclo(d-Trp-l-Pro) and cyclo(d-Trp-d-Pro) - on heart and ion-channel activity. The effects on L-type Ca2+-channel, Na+-channel and inward rectifier K+-channel activity were determined by using the whole-cell patch-clamp technique on myocytes of guinea-pig origin. Dependence on the membrane potential in terms of Ca2+-channel activity was also investigated. A modified Langendorff method was used to determine the effects of the isomers on heart rate, coronary flow, duration of ventricular tachycardia and arrhythmia, time to sinus rhythm and QRS interval on the rat isolated heart. Cyclo(l-Trp-l-Pro), cyclo(l-Trp-d-Pro) and cyclo(d-Trp-d-Pro), 100 μm, showed agonism towards Ca2+-channel activity, while cyclo(d-Trp-l-Pro) caused a blockage of the current. The action of cyc...

Research paper thumbnail of The effects of creatine on the retrogradely perfused isolated rat heart

Journal of Pharmacy and Pharmacology, 2002

Although the role of creatine in muscle metabolism is well understood, there is still uncertainty... more Although the role of creatine in muscle metabolism is well understood, there is still uncertainty as to its effects at supplemented levels. With this in mind, this study was designed to investigate the direct effects of commercially available creatine on the isolated rat heart, retrogradely perfused and infused with varying concentrations of creatine (1.25, 2.5, 5 and 10 mM) to determine its effects on heart rate, coronary flow and ventricular pressure. Furthermore, tissue from these hearts was used to investigate the cardiotoxic potential of supplemented levels of creatine. Results indicate that creatine directly improves the functioning of the heart under normal conditions with respect to heart rate and ventricular pressure, but may be detrimental to the functioning of energy-deprived hearts. It also showed no cardiotoxic properties since it increased the baseline levels of adenosine triphosphate (ATP) and decreased the levels of isocitrate dehydrogenase (ICD), indicating a decrea...

Research paper thumbnail of Formulation Development and Stability Studies of Aqueous Metronidazole Benzoate Suspensions Containing Various Suspending Agents

Drug Development and Industrial Pharmacy, 2007

Metronidazole is a synthetic antibacterial and antiprotozoan agent. Crystallization occurs in aqu... more Metronidazole is a synthetic antibacterial and antiprotozoan agent. Crystallization occurs in aqueous metronidazole benzoate suspensions caused by an anhydrate to monohydrate conversion. This study aimed to develop an aqueous metronidazole benzoate suspension that does not exhibit this hydration and the accompanying crystal growth. Four suspending agent systems were evaluated. Xanthan gum and Avicel RC-591 (a combination of microcrystalline cellulose and carboxymethylcellulose sodium) were found to be the suspending agents that resulted in optimal formulation properties. Monohydrate formation did not occur in product containing Avicel RC-591, indicating that suspending agents may exert a positive effect on metronidazole benzoate suspension stability.

Research paper thumbnail of The Properties, Formation, and Biological Activity of 2,5-Diketopiperazines

Elsevier eBooks, 2010

... further investigation of their clinical potential essential. Related research. Biological act... more ... further investigation of their clinical potential essential. Related research. Biological activity of selected tyrosine-containing 2,5-diketopiperazines. G Kilian, H Jamie, SCA Brauns, K Dyason, PJ Milne in Die Pharmazie (2005). ...

Research paper thumbnail of Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala)

PubMed, Mar 1, 2013

Cyclic dipeptides have been well characterized for their biological activity, including antimicro... more Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

Research paper thumbnail of The effects of creatine on the retrogradely perfused isolated rat heart

Journal of Pharmacy and Pharmacology, 2002

Although the role of creatine in muscle metabolism is well understood, there is still uncertainty... more Although the role of creatine in muscle metabolism is well understood, there is still uncertainty as to its effects at supplemented levels. With this in mind, this study was designed to investigate the direct effects of commercially available creatine on the isolated rat heart, retrogradely perfused and infused with varying concentrations of creatine (1.25, 2.5, 5 and 10 mM) to determine its effects on heart rate, coronary ow and ventricular pressure. Furthermore, tissue from these hearts was used to investigate the cardiotoxic potential of supplemented levels of creatine. Results indicate that creatine directly improves the functioning of the heart under normal conditions with respect to heart rate and ventricular pressure, but may be detrimental to the functioning of energy-deprived hearts. It also showed no cardiotoxic properties since it increased the baseline levels of adenosine triphosphate (ATP) and decreased the levels of isocitrate dehydrogenase (ICD), indicating a decrease in cellular death compared with nonsupplemented control hearts.

Research paper thumbnail of Hepatotoxicity of the isomers of cyclo(Trp-Pro)

PubMed, Sep 1, 2002

The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage ... more The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage in various pharmacological fields, had not been assessed. Further studies on the isomers of this cyclic dipeptide (cyclo(L-Trp-L-Pro), cyclo-(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro)) revealed further biological activities. The assessment of hepatotoxicity of these isomers was thus warranted. In vitro screens were performed on primary isolated rat hepatocytes, the Chang liver and N-2-alpha cell lines. In vivo screening involved the assessment of serum levels of lactate dehydrogenase, aspartate transaminase, ATP, Ca2+ and albumin after intraperitoneal injection over a 1 and 5 day period in the rat model. Liver samples were also obtained for the assessment of lipid peroxidation. It was found that only cyclo(D-Trp-L-Pro) was hepato-specific in its action, while the other isomers were not. The greatest effect on any biochemical or physiological parameter was noted after 5 days. LDH secretion was greatly increased in the presence of cyclo(L-Trp-L-Pro) and cyclo-(L-Trp-D-Pro) (p < 0.05). Significantly increased levels of lipid peroxidation were observed in all the isomer-treated samples (p < 0.05), while Ca2+ concentrations were decreased at day 5. Decreased protein synthesis was noted in the presence of all the isomers at day 1. These results indicate the potential harm involved in the administration of the isomers, which may limit their potential usage in the treatment of various diseases.

Research paper thumbnail of The effect of the isomers of cyclo(Trp-Pro) on heart and ion-channel activity

Journal of Pharmacy and Pharmacology, Dec 1, 2002

Research paper thumbnail of Optimization of selected liposome-encapsulated diketopiperazines

Journal of Drug Delivery Science and Technology, 2014

Response surface methodology (RSM) is an effective way to optimize various processes and formulat... more Response surface methodology (RSM) is an effective way to optimize various processes and formulations were investigators are able to determine how variables influence the formulation by assessing interaction effects in order to obtain an optimum formulation. Cyclic dipeptides have been shown to inhibit tumor cells but problems with their physicochemical characteristics have limited further development of these compounds clinically. The aim was to optimize a liposome-based drug delivery system incorporating cyclo(His-Gly) and cyclo(His-Ala) using response surface methodology. Liposomes, containing varying compositions of phosphatidylcholine, cholesterol, stearylamine, vitamin E and PEG2000-phosphatidylethanolamine were prepared according to the thin film hydration and extrusion method. Drugs were passively encapsulated and separated from free drug using Sephadex G50 columns. RSM, utilizing a central composite rotatable design (CCRD) was used to assess the influence of selected variables on encapsulation, uptake, membrane leakage, polydispersity and zeta potential. A quadratic model was used to fit data for all responses. The most significant interaction was between cholesterol and stearylamine content with cellular uptake, indicating that these parameters cannot be altered independently of each other. Optimization of the formulation yielded stable liposomes with an average encapsulation of 0.123 mg drug/mg lipid.

Research paper thumbnail of Biological activity of selected tyrosine-containing 2,5-diketopiperazines

PubMed, Apr 1, 2005

The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with ... more The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with respect to their biological activity. Investigations using the whole-cell patch-clamp technique testing the effects of 100 microM cyclic dipeptide on ion channels, revealed reversible voltage-dependant blockade for cTT, while cPT exhibited irreversible time-dependant blockade of L-type calcium channels. The isolated retrogradely-perfused rat heart was used to determine the effects of 100 microM of either cTT or cPT on heart rate (HR), coronary flow rate (CFR), left ventricular systolic pressure (LVSP) and cardiac conduction speed. Results indicated opposing effects for the two compounds, where cTT increased HR and CF while cPT decreased HR, CF, LVSP as well as conduction speed. Other biological investigations included opioid binding and anti-neoplastic assays. Competitive binding curves, using tritiated DAMGO, revealed significant binding to micro-opioid receptors with IC50 values for cTT and cPT being 0.82 microM and 69.7 microM respectively. Anti-neoplastic activity was tested using three cultured cell lines: HT-29, MCF-7 and HeLa which were exposed to 2.5 mM cyclic dipeptide or 0.1 mM melphalan as a positive control. While cTT showed little activity against these lines, cPT resulted in as much as a 75.6% growth inhibition of MCF-7 cells, while also being active against HeLa (73.4% inhibition) and HT-29 (60.6%). The results indicate potential biological activity, showing a need for more investigation into tyrosine containing cyclic dipeptides and their analogues as potential bioactive compounds.

Research paper thumbnail of The development of folate-functionalised palladium nanoparticles for folate receptor targeting in breast cancer cells

Nanotechnology

Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A no... more Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A non-toxic concentration of folate-conjugated palladium-based nanoparticles was used to target the overexpressed folate receptor on breast cancer cells. The folate-conjugated nanoparticles were tailored to accumulate selectively in cancer cells relative to normal cells via the folate receptor. The MDA-MB-231, MDA-MB-468, MCF-7 breast cancer cell lines, and MCF-10A normal cell lines were used in the study. Qualitative and quantitative analysis of nanoparticle cellular uptake and accumulation was conducted using transmission electron microscopy and inductively coupled plasma-optical emission spectroscopy. The findings proved that folate-conjugated palladium nanoparticles successfully and preferentially accumulated in breast cancer cells. We conclude that folate-conjugated palladium nanoparticles can be potentially used to target breast cancer cells for radiopharmaceutical applications.

Research paper thumbnail of Learning and teaching in the time of COVID-19

Research paper thumbnail of The Introduction of Process Analytical Technology, Using Near Infrared Analysis, to a Pharmaceutical Blending Process

This study investigates the use of a laboratory scale blender fitted with a near infrared probe t... more This study investigates the use of a laboratory scale blender fitted with a near infrared probe to monitor lubricant uniformity in a granule blend. A software method was developed to monitor the change in absorbance at significant wavelengths for the granule and lubricant (magnesium stearate) as the blend proceeded in real-time. The standard deviation of the absorbance was plotted as a function of time to monitor the change in the blend. With near infrared spectra, when a process is complete, the spectra will not change, therefore the standard deviation will be small [6]. To verify this, the blend was sampled using a standard sampling method and analyzed with an atomic absorption method for magnesium stearate to ascertain the distribution in the blend. Blends sampled at the predetermined time intervals were well blended when the standard deviation of the absorbance was low and poorly blended when the standard deviation of the absorbance was high, thus verifying the near infrared pre...

Research paper thumbnail of Academia 2.0

Some days I have to stop myself when I’m prompted to say, “When I was a student …” in response to... more Some days I have to stop myself when I’m prompted to say, “When I was a student …” in response to a student request that would have seemed completely out of line 20 years ago. As academics, we find ourselves in an ever changing environment where the demand for flexibility almost requires that each of us take regular yoga classes.

Research paper thumbnail of Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala)

Pharmazie

Cyclic dipeptides have been well characterized for their biological activity, including antimicro... more Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

Research paper thumbnail of Antimicrobial activity of liposome encapsulated cyclo(L-tyrosyl-L-prolyl)

Pharmazie

Various studies have shown the potentially beneficial biological activities of cyclic dipeptides ... more Various studies have shown the potentially beneficial biological activities of cyclic dipeptides and in particular, cyclo(L-tyrosyl-L-prolyl) (cyclo(Tyr-Pro)) has shown fair antibacterial activity in vitro. This study aimed to determine if liposome encapsulation would have any significant effects on the antibacterial activity of this compound. The thin-film hydration method with extrusion was used to produce small unilamellar vesicles containing cyclo(Tyr-Pro) that were shown to have an average encapsulation of 9.4% with a mean particle size of 160.4 nm. Minimum inhibitory concentrations tested against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Bacillus subtillis were shown to be lower in liposome encapsulated cyclo(Tyr-Pro) than for the free form, while no antimicrobial activity was noted for either encapsulated nor non-encapsulated drug against the fungus Candida albicans or two methicillin-resistant strains of Staphylococcus aureus (MRSA). A positive control of liposome encapsulated amoxicillin was shown to be extremely active against both MRSA strains. The results confirm that liposome encapsulation has the potential to enhance activity as well as to overcome bacterial resistance towards current antibacterial agents.

Research paper thumbnail of The medicinal chemistry of aromatic cyclic dipeptides : cyclo(Tyr-Tyr) and cyclo(Phe-Tyr) /

Research paper thumbnail of Biological activity of tyrosine-containing 2,5-diketopiperazines

Research paper thumbnail of The synthesis and anticancer activity of selected diketopiperazines

Research paper thumbnail of The biological activity of the histidine-containing diketopiperazines cyclo(His-Ala) and cyclo(His-Gly)

Peptides, 2006

Two cyclic dipeptides, cyclo(His-Ala) and cyclo(His-Gly,) were synthesized from their linear coun... more Two cyclic dipeptides, cyclo(His-Ala) and cyclo(His-Gly,) were synthesized from their linear counterparts and their structures elucidated using standard elucidation techniques. Molecular modeling and predictive NMR results indicated that the majority of energetically favourable conformers adopted a boat conformation with respect to the diketopiperazine ring. Cyclo(His-Ala), at concentrations of 100 mM inhibited the growth, in vitro, of various cancer cell lines, including HT-29, MCF-7 and HeLa carcinoma cells while cyclo(His-Gly) inhibited the growth of MCF-7 cells. While the antibacterial potential of these two compounds was limited, both cyclic dipeptides significantly inhibited the growth of C. albicans. Both compounds at a concentration of 100 mM resulted in a decrease in heart rate, coronary flow rate and left ventricular systolic pressure in the isolated rat heart. Inhibition of thrombin, amounting to a 63.3% and 36.7% reduction in the rate of fibrin formation, was noted for cyclo(His-Ala) and cyclo(His-Gly), respectively. While cyclo(His-Ala) showed no notable effects on platelet aggregation, cyclo(His-Gly) significantly inhibited both pathways tested with greatest effects on thrombin-induced platelet aggregation, yielding an IC 50 of 0.0662 mM (R 2 = 0.989). The results of the anticancer and hematological studies indicate that histidine-containing diketopiperazines have potential as a novel group of cytotoxic agents with antithrombotic effects.

Research paper thumbnail of The effect of the isomers of cyclo(Trp-Pro) on heart and ion-channel activity

Journal of Pharmacy and Pharmacology, 2002

Cyclo(l-Trp-l-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. Th... more Cyclo(l-Trp-l-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. The aim of the study was to determine the effects of the isomers of cyclo(Trp-Pro) - cyclo(l-Trp-l-Pro), cyclo(l-Trp-d-Pro), cyclo(d-Trp-l-Pro) and cyclo(d-Trp-d-Pro) - on heart and ion-channel activity. The effects on L-type Ca2+-channel, Na+-channel and inward rectifier K+-channel activity were determined by using the whole-cell patch-clamp technique on myocytes of guinea-pig origin. Dependence on the membrane potential in terms of Ca2+-channel activity was also investigated. A modified Langendorff method was used to determine the effects of the isomers on heart rate, coronary flow, duration of ventricular tachycardia and arrhythmia, time to sinus rhythm and QRS interval on the rat isolated heart. Cyclo(l-Trp-l-Pro), cyclo(l-Trp-d-Pro) and cyclo(d-Trp-d-Pro), 100 μm, showed agonism towards Ca2+-channel activity, while cyclo(d-Trp-l-Pro) caused a blockage of the current. The action of cyc...

Research paper thumbnail of The effects of creatine on the retrogradely perfused isolated rat heart

Journal of Pharmacy and Pharmacology, 2002

Although the role of creatine in muscle metabolism is well understood, there is still uncertainty... more Although the role of creatine in muscle metabolism is well understood, there is still uncertainty as to its effects at supplemented levels. With this in mind, this study was designed to investigate the direct effects of commercially available creatine on the isolated rat heart, retrogradely perfused and infused with varying concentrations of creatine (1.25, 2.5, 5 and 10 mM) to determine its effects on heart rate, coronary flow and ventricular pressure. Furthermore, tissue from these hearts was used to investigate the cardiotoxic potential of supplemented levels of creatine. Results indicate that creatine directly improves the functioning of the heart under normal conditions with respect to heart rate and ventricular pressure, but may be detrimental to the functioning of energy-deprived hearts. It also showed no cardiotoxic properties since it increased the baseline levels of adenosine triphosphate (ATP) and decreased the levels of isocitrate dehydrogenase (ICD), indicating a decrea...

Research paper thumbnail of Formulation Development and Stability Studies of Aqueous Metronidazole Benzoate Suspensions Containing Various Suspending Agents

Drug Development and Industrial Pharmacy, 2007

Metronidazole is a synthetic antibacterial and antiprotozoan agent. Crystallization occurs in aqu... more Metronidazole is a synthetic antibacterial and antiprotozoan agent. Crystallization occurs in aqueous metronidazole benzoate suspensions caused by an anhydrate to monohydrate conversion. This study aimed to develop an aqueous metronidazole benzoate suspension that does not exhibit this hydration and the accompanying crystal growth. Four suspending agent systems were evaluated. Xanthan gum and Avicel RC-591 (a combination of microcrystalline cellulose and carboxymethylcellulose sodium) were found to be the suspending agents that resulted in optimal formulation properties. Monohydrate formation did not occur in product containing Avicel RC-591, indicating that suspending agents may exert a positive effect on metronidazole benzoate suspension stability.