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 preparation of BODIPY and porphyrin dyes and their cyclodextrin inclusion complexes and Pluronic® F-127 encapsulation micelles for use in PDT and PACT
- Authors: Molupe, Nthabeleng
- Date: 2019
- Subjects: Dyes and dyeing -- Chemistry , Drug delivery systems , Fluorescence spectroscopy , Cancer -- Photochemotherapy , Photosensitizing compounds -- Therapeutic use , Cyclodextrins -- Biotechnology , Nanoparticles
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117574 , vital:34528
- Description: Several novel BODIPY dyes ((4,4′-difluoro-1,7-tetramethyl-3,5-(3-dithiophene)-2,6-diiodo-8-(4-dimethylamino)-4-bora-3a,4a-diaza-s-indacene (1c), 4,4′-difluoro-1,7-tetramethyl-3,5-(3 dithiophene)-2,6-diiodo-8-(4-methylthio)-4-bora-3a,4a-diaza-s-indacene (3c) and 4,4′-difluoro-1,7-tetramethyl-3,5-(4-dibenzyloxybenzene)-2,6-diiodo-8-(4-methylbenzoate)-4 bora-3a,4a-diaza-s-indacene (4c)) and porphyrins (tetraacenaphthylporphyrin (7a) and Sn(IV) tetraacenaphthylporphyrin (7b)) were synthesized and characterized. Previously reported BODIPY dyes (4,4′-difluoro-1,7-tetramethyl-3,5-(2-dihydroxy)-2,6-diiodo-8-(4-bromo)-4-bora-3a,4a-diaza-s-indacene (5) and 4,4′-difluoro-1,7-tetramethyl-3,5-(2-dithiophene)-2,6-diiodo-8-(phenyl)-4-bora-3a,4a-diaza-s-indacene (6)) were also used. Pluronic® F-127 and cyclodextrins were used as solubilizing drug delivery agents for the synthesized BODIPY dyes. The encapsulation of BODIPY dyes with Pluronic® F-127 micelles improved the water solubility of the BODIPY 5. Further modification of Pluronic® F-127 by coating with folate-functionalized chitosan for targeted delivery of BODIPY 1c and 6 was explored. The BODIPY dyes and their encapsulation complexes exhibited significant inhibition of human MCF-7 breast cancer cell growth. When cyclodextrins were used as nanocarriers, the inclusion complexes of BODIPY 4c with mβCD were found to enhance the water-solubility of the dye. Greater photoinactivation of Staphylococcus aureus was observed for the inclusion complexes when compared to the effect of solutions of non-complexed BODIPY 4c. The cyclodextrin inclusion complexes of porphyrin 7b with mβCD were also found to enhance the water-solubility of 7b. When the photodynamic effect was evaluated, solutions of the porphyrin alone and their inclusion complexes were found to have significant photodynamic effects against human MCF-7 breast cancer cells.
- Full Text:
- Date Issued: 2019
- Authors: Molupe, Nthabeleng
- Date: 2019
- Subjects: Dyes and dyeing -- Chemistry , Drug delivery systems , Fluorescence spectroscopy , Cancer -- Photochemotherapy , Photosensitizing compounds -- Therapeutic use , Cyclodextrins -- Biotechnology , Nanoparticles
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117574 , vital:34528
- Description: Several novel BODIPY dyes ((4,4′-difluoro-1,7-tetramethyl-3,5-(3-dithiophene)-2,6-diiodo-8-(4-dimethylamino)-4-bora-3a,4a-diaza-s-indacene (1c), 4,4′-difluoro-1,7-tetramethyl-3,5-(3 dithiophene)-2,6-diiodo-8-(4-methylthio)-4-bora-3a,4a-diaza-s-indacene (3c) and 4,4′-difluoro-1,7-tetramethyl-3,5-(4-dibenzyloxybenzene)-2,6-diiodo-8-(4-methylbenzoate)-4 bora-3a,4a-diaza-s-indacene (4c)) and porphyrins (tetraacenaphthylporphyrin (7a) and Sn(IV) tetraacenaphthylporphyrin (7b)) were synthesized and characterized. Previously reported BODIPY dyes (4,4′-difluoro-1,7-tetramethyl-3,5-(2-dihydroxy)-2,6-diiodo-8-(4-bromo)-4-bora-3a,4a-diaza-s-indacene (5) and 4,4′-difluoro-1,7-tetramethyl-3,5-(2-dithiophene)-2,6-diiodo-8-(phenyl)-4-bora-3a,4a-diaza-s-indacene (6)) were also used. Pluronic® F-127 and cyclodextrins were used as solubilizing drug delivery agents for the synthesized BODIPY dyes. The encapsulation of BODIPY dyes with Pluronic® F-127 micelles improved the water solubility of the BODIPY 5. Further modification of Pluronic® F-127 by coating with folate-functionalized chitosan for targeted delivery of BODIPY 1c and 6 was explored. The BODIPY dyes and their encapsulation complexes exhibited significant inhibition of human MCF-7 breast cancer cell growth. When cyclodextrins were used as nanocarriers, the inclusion complexes of BODIPY 4c with mβCD were found to enhance the water-solubility of the dye. Greater photoinactivation of Staphylococcus aureus was observed for the inclusion complexes when compared to the effect of solutions of non-complexed BODIPY 4c. The cyclodextrin inclusion complexes of porphyrin 7b with mβCD were also found to enhance the water-solubility of 7b. When the photodynamic effect was evaluated, solutions of the porphyrin alone and their inclusion complexes were found to have significant photodynamic effects against human MCF-7 breast cancer cells.
- Full Text:
- Date Issued: 2019
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