Synthesis of pH responsive carriers for pulmonary drug delivery of anti-tuberculosis therapeutics: mesoporous silica nanoparticles and gelatin nanoparticles
- Authors: Ngoepe, Mpho Phehello
- Date: 2019
- Subjects: Drug delivery systems , Pulmonary pharmacology , Nanosilicon , Nanomedicine , Nanoparticles , Mesoporous materials , Silica , Tuberculosis -- Treatment
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/76519 , vital:30590
- Description: Pulmonary drug delivery has historically been used as a route for delivery of therapeutics for respiratory disease management. However, while there are many advantages, there are also some serious limitations, arising mostly from the physical aspects of the inhaler devices. This is more profound when the devices are the driving force for controlling particle size generation, which results in non-uniform particles that end up being swallowed/wasted/expelled. One promising solution to overcome this limitation is to pre-formulate nano/microscale particles with a high degree of manufacturing control. Nanomedicine has advanced such that there are already several nanoparticle formulations commercially available. In the case of tuberculosis treatment, there is an opportunity not only to examine the use of nanoparticles for inhalation therapy, but to take advantage of the fact that the physiochemical environment of diseased tissue is significantly different to health lung tissue (lower pH and increased enzyme concentrations). We formulated two series of nanoparticles, whose design included moieties that could respond to pH and enzymes. To address variability, a Box-Behnken statistical approach was followed to construct mesoporous silica nanoparticles. These “hard nanoparticles” can entrap both lipophilic and hydrophilic drugs and were coated with a pH-sensitive hydrazone linker. It was observed that pH, calcination temperature and ratio of water to silica source played the greatest role, not only in controlling the physicochemical properties of the nanoparticles but also the drug release rate. A second series of nanoparticles were synthesized based on gelatin. This was done partly to add support the comparison of hard (inorganic silica) versus soft, organic particles, but also to enable enzymatic degradation and drug release. Again, diseased lung tissue expresses increased concentrations of gelatinase enzymes that could be used to stimulate drug release at the site of the disease. In addition, it was observed that the non-ionic surfactant C12E10 could interact with the protein via hydrophobic interactions thus affecting the gelatin folding. The folding states affected crosslinking with the pH responsive linker, which in turn affected the rate of drug release. To support the synthetic work, we sought to develop a unique 3D lung model directly from MRI data of tuberculosis infected lungs. This would not only permit the evaluation of our nanoparticles but could be used as a proxy for in-vivo studies in future to predict lung deposition in diseased lung. Thus, this study shows that it is possible to synthesize pH and enzyme sensitive nanoparticles for pulmonary drug delivery in the treatment and management of pulmonary tuberculosis. These particles could be loaded with either hydrophobic or hydrophilic drugs and their distribution in the airway modelled using an in-silico 3D model based on real data. Further development and verification of these results should improve treatment for pulmonary diseases and conditions such as tuberculosis. This is especially urgent in the face of multi-drug resistance and poor side effects profiles for current treatment.
- Full Text:
- Date Issued: 2019
- Authors: Ngoepe, Mpho Phehello
- Date: 2019
- Subjects: Drug delivery systems , Pulmonary pharmacology , Nanosilicon , Nanomedicine , Nanoparticles , Mesoporous materials , Silica , Tuberculosis -- Treatment
- Language: English
- Type: text , Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10962/76519 , vital:30590
- Description: Pulmonary drug delivery has historically been used as a route for delivery of therapeutics for respiratory disease management. However, while there are many advantages, there are also some serious limitations, arising mostly from the physical aspects of the inhaler devices. This is more profound when the devices are the driving force for controlling particle size generation, which results in non-uniform particles that end up being swallowed/wasted/expelled. One promising solution to overcome this limitation is to pre-formulate nano/microscale particles with a high degree of manufacturing control. Nanomedicine has advanced such that there are already several nanoparticle formulations commercially available. In the case of tuberculosis treatment, there is an opportunity not only to examine the use of nanoparticles for inhalation therapy, but to take advantage of the fact that the physiochemical environment of diseased tissue is significantly different to health lung tissue (lower pH and increased enzyme concentrations). We formulated two series of nanoparticles, whose design included moieties that could respond to pH and enzymes. To address variability, a Box-Behnken statistical approach was followed to construct mesoporous silica nanoparticles. These “hard nanoparticles” can entrap both lipophilic and hydrophilic drugs and were coated with a pH-sensitive hydrazone linker. It was observed that pH, calcination temperature and ratio of water to silica source played the greatest role, not only in controlling the physicochemical properties of the nanoparticles but also the drug release rate. A second series of nanoparticles were synthesized based on gelatin. This was done partly to add support the comparison of hard (inorganic silica) versus soft, organic particles, but also to enable enzymatic degradation and drug release. Again, diseased lung tissue expresses increased concentrations of gelatinase enzymes that could be used to stimulate drug release at the site of the disease. In addition, it was observed that the non-ionic surfactant C12E10 could interact with the protein via hydrophobic interactions thus affecting the gelatin folding. The folding states affected crosslinking with the pH responsive linker, which in turn affected the rate of drug release. To support the synthetic work, we sought to develop a unique 3D lung model directly from MRI data of tuberculosis infected lungs. This would not only permit the evaluation of our nanoparticles but could be used as a proxy for in-vivo studies in future to predict lung deposition in diseased lung. Thus, this study shows that it is possible to synthesize pH and enzyme sensitive nanoparticles for pulmonary drug delivery in the treatment and management of pulmonary tuberculosis. These particles could be loaded with either hydrophobic or hydrophilic drugs and their distribution in the airway modelled using an in-silico 3D model based on real data. Further development and verification of these results should improve treatment for pulmonary diseases and conditions such as tuberculosis. This is especially urgent in the face of multi-drug resistance and poor side effects profiles for current treatment.
- Full Text:
- Date Issued: 2019
The contribution of psychogenic factors limiting prolonged work performed at different relative intensities
- Authors: Rorke, Stafford Conroy
- Date: 1986
- Subjects: Physical fitness -- Measurement , Physical fitness -- Psychological aspects , Work measurement , Work -- Psychological aspects
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:5103 , http://hdl.handle.net/10962/d1004772 , Physical fitness -- Measurement , Physical fitness -- Psychological aspects , Work measurement , Work -- Psychological aspects
- Description: This study investigated the physiological and psychological limitations to prolonged work performed at different relative intensities, through the use of an eclectic integrative methodology. Ten young male caucasian subjects (mean V0₂ max. 60,0 ml.kg⁻¹.min⁻¹ ± 7,9) were randomly exposed to treadmill runs at each of four relative intensities, namely 55%, 65%, 75% and 85% of V0₂ maximum, with the instruction to run to the point of subjective discomfort at which they were no longer willing to continue. Physiological measures of oxygen consumption (V0₂), heart rate (HR), respiratory exchange ratio (R) , minute ventilation volume (Vi), breathing frequency (Vf), tidal volume (Vt) and psychological measures of Ratings of Perceived Exertion (RPE), Perceived Thermal Comfo·rt (PTC), Perceived Pain and Perceived Fatigue were recorded throughout the protocol. The relative intensity was held constant by slight decreases in treadmill speed as subjects fatigued, and through feedback from an on-line oxygen consumption computer-aided data acquisition system. Significant increases in both physiological and psychological measures occurred with increases in relative intensity (p<0,05). HR and Vf increased overtime (p<0,05) whilst Rand Vt decreased over time (p < 0,05) . All psychological ratings increased in intensity over time (p < 0,05). Mean endurance times to exhaustion were 243 minutes ± 70 at 55% relative intensity, 159 minutes ±37 at 65%, 96 minutes ±25 at 75 % and 23 minutes +- 8 at 85%, being within the range reported by earlier researchers . A regression equation for prediction of endurance time given a known relative intensity was developed for this sample: % V0₂ max. = 117,8 + (-10,6 x LN (time)) (where r = -0,91) Convergence rankings indicate the greater contribution of local factors in the overall gestalt of perceived exertion, pain and fatigue, with biomechanical limitations to prolonged work (running) strongly implicated . High inter correlations between psychological rating scales suggest the use of the scale considered most applicable to the task at hand and the psychological response measure required. A coefficient of multiple correlation of 0,94 established the close interrelationship amongst the physiological and psychological parameters measured. Pre- and post-test Fatigue Cluster Analysis questionnaires indicated that the most important clusters contributing toward the sensation of fatigue and subsequent decision to cease activity were Task Aversion and General Fatigue (r = 0,96), followed by Leg Fatigue and Thirst. Motivation, the task at hand and an attainable goal appear to be important considerations in prolonged work performance. Relative intensity appears a valid tool for use in prolonged work studies due to its high predictive capacity for endurance performance times (r=-0,91). It is concluded that workloads considerably below 55% of maximal aerobic capacity are indicated as acceptable workloads for an 8 hour working day.
- Full Text:
- Date Issued: 1986
- Authors: Rorke, Stafford Conroy
- Date: 1986
- Subjects: Physical fitness -- Measurement , Physical fitness -- Psychological aspects , Work measurement , Work -- Psychological aspects
- Language: English
- Type: Thesis , Masters , MA
- Identifier: vital:5103 , http://hdl.handle.net/10962/d1004772 , Physical fitness -- Measurement , Physical fitness -- Psychological aspects , Work measurement , Work -- Psychological aspects
- Description: This study investigated the physiological and psychological limitations to prolonged work performed at different relative intensities, through the use of an eclectic integrative methodology. Ten young male caucasian subjects (mean V0₂ max. 60,0 ml.kg⁻¹.min⁻¹ ± 7,9) were randomly exposed to treadmill runs at each of four relative intensities, namely 55%, 65%, 75% and 85% of V0₂ maximum, with the instruction to run to the point of subjective discomfort at which they were no longer willing to continue. Physiological measures of oxygen consumption (V0₂), heart rate (HR), respiratory exchange ratio (R) , minute ventilation volume (Vi), breathing frequency (Vf), tidal volume (Vt) and psychological measures of Ratings of Perceived Exertion (RPE), Perceived Thermal Comfo·rt (PTC), Perceived Pain and Perceived Fatigue were recorded throughout the protocol. The relative intensity was held constant by slight decreases in treadmill speed as subjects fatigued, and through feedback from an on-line oxygen consumption computer-aided data acquisition system. Significant increases in both physiological and psychological measures occurred with increases in relative intensity (p<0,05). HR and Vf increased overtime (p<0,05) whilst Rand Vt decreased over time (p < 0,05) . All psychological ratings increased in intensity over time (p < 0,05). Mean endurance times to exhaustion were 243 minutes ± 70 at 55% relative intensity, 159 minutes ±37 at 65%, 96 minutes ±25 at 75 % and 23 minutes +- 8 at 85%, being within the range reported by earlier researchers . A regression equation for prediction of endurance time given a known relative intensity was developed for this sample: % V0₂ max. = 117,8 + (-10,6 x LN (time)) (where r = -0,91) Convergence rankings indicate the greater contribution of local factors in the overall gestalt of perceived exertion, pain and fatigue, with biomechanical limitations to prolonged work (running) strongly implicated . High inter correlations between psychological rating scales suggest the use of the scale considered most applicable to the task at hand and the psychological response measure required. A coefficient of multiple correlation of 0,94 established the close interrelationship amongst the physiological and psychological parameters measured. Pre- and post-test Fatigue Cluster Analysis questionnaires indicated that the most important clusters contributing toward the sensation of fatigue and subsequent decision to cease activity were Task Aversion and General Fatigue (r = 0,96), followed by Leg Fatigue and Thirst. Motivation, the task at hand and an attainable goal appear to be important considerations in prolonged work performance. Relative intensity appears a valid tool for use in prolonged work studies due to its high predictive capacity for endurance performance times (r=-0,91). It is concluded that workloads considerably below 55% of maximal aerobic capacity are indicated as acceptable workloads for an 8 hour working day.
- Full Text:
- Date Issued: 1986
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