Design, synthesis, manufacture, characterization and evaluation of lipid nanocapsules in chitosan-iota-carrageenan based hydrogel scaffold as a potential anti-Covid-19 drug delivery system
- Authors: Mukubwa, Grady Kathondo
- Date: 2022-10-14
- Subjects: Nanocapsules Design , Hydrogel , COVID-19 (Disease) , Characterization , Drug delivery systems
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/364955 , vital:65665
- Description: Covid-19 is a deadly viral disease that has been rampant around the world since 2019. Although the successful introduction of the vaccine has reduced the spread of covid-19, new cases and deaths are still being recorded. To date, no specific curative antiviral treatment has been approved for covid-19. However, many existing antiviral drugs have been and are still being studied against covid-19 and some of them, such as Remdesivir, have shown promise and could be repurposed to treat this infection. Unfortunately, antiviral drugs are prone to resistance as most of them have poor biopharmaceutical properties, including low solubility, permeability and bioavailability, which could hinder any clinical success. Recent advances in nanotechnology-based delivery systems have made it possible to improve the biopharmaceutical properties of many drugs, especially those of poorly water-soluble drugs, by formulating them as lipid nanoparticles (LNP). Thus, in order to contribute to the fight against covid-19, this work aimed to develop Lipid Nanocapsules (LNC), based on some natural raw materials, which could improve the biopharmaceutical properties of antiviral drugs. In addition, since covid-19 infection is mainly respiratory, this work also aimed to fabricate a targeted delivery system based on a hydrogel capable of entrapping LNC and ensuring their efficient deposition and release in the lungs. The LNC consisted of a mixture of medium-chain triglycerides oil (MCT oil), crude soy lecithin, tween 80, NaCl and water, while the hydrogel consisted of a chitosan-grafted-iota carrageenan-grafted-poly (acrylamide-co-acrylic acid) system (CS-iCar-p (AAm-Co-AA)). Efavirenz (EFV), a drug with very low water solubility that has recently been demonstrated to have the potential to influence sars-cov-2 life cycle through different targets (3CLP, RdRp, Hellicase, 3’to5’exonuclease, 2’-O-ribose methyltransferase and EndoRNAse), was chosen as the model drug to evaluate the developed delivery system. The combination of LNP and hydrogel results in a delivery system known as the LNP-hydrogel composite, an emerging area of research in the field of drug delivery. To date, no research has reported the design and fabrication of an LNC-CS-iCar-p (AAm-Co-AA) hydrogel composite that could effectively deliver an antiviral drug to the lungs in addition to its advantages in terms of biological activities. Prior to the design of experiment, EFV solubility was assessed in water, labrafac lipophile 1349 and MCT oil. After that, the Design Expert Software version 13 was used to design the different experiments performed in this work. The I-optimal mixture design of experiments was performed for both LNC preparation and CS-iCar-p (AAm-Co-AA) hydrogel synthesis to study the impact of raw materials on the characteristics of these delivery systems. LNC were prepared using the phase inversion method while the free radical precipitation graft copolymerization method was used to synthesize hydrogel. In order to build polynomial models that could predict the amount of drug both LNC and CS-iCar-p (AAm-Co-AA) hydrogel can entrap, a D-optimal (custom) randomized design was performed. Moreover, various characterization techniques were used to investigate the physicochemical properties of the developed delivery systems. Thereafter, drug release studies were performed using a 1% sodium lauryl sulfate solution adjusted to either pH 4 or 7. Solubility studies revealed that EFV was more soluble in labrafac lipophile 1349 and in MCT oil than in water; therefore, given its affordability, MCT oil was used for the LNC formulation. The design of experiment carried out allowed the construction of polynomial models that could predict, on the one hand, the droplet size, the polydispersity index and the Zeta potential of LNC, which were respectively around 50nm, below 0.2 and below -33. On the other hand, the model could predict the swelling capacity of the synthesized hydrogel, which was optimised to about 30,000% (300 g of water to 1 g of hydrogel). This turned out to be influenced by the proportion of polymers, the ratio of monomers as well as the concentration of the cross-linking agent. In addition, the characterization techniques further supported the improvement of EFV solubility by highlighting its conversion into its amorphous state after encapsulation in LNC. They also confirmed successful synthesis of CS-iCar-p (AAm-co-AA) hydrogel. LNC were able to encapsulate about 87% of EFV while the synthesized CS-iCar-p (AAm-co-AA) hydrogel entrapped around 53% of EFV encapsulated in LNC. While LNC were able to release 42% and 27% of EFV after 74 hours in a 1% sodium lauryl sulfate solution (SLS) at pH 7 and pH 4 respectively, the LNC-CS-iCar-p (AAm-co-AA) hydrogel composite released about 50% and 40% of the drug after 9 days in the same release medium. Interestingly, the chemical integrity of the drug was preserved throughout the manufacturing process up to after its release, suggesting that the developed LNC-CS-iCar-p (AAm-co-AA) hydrogel composite could be used as a novel potential anticovid-19 drugs delivery system. , Thesis (MSc) -- Faculty of Science, Chemistry, 2022
- Full Text:
- Date Issued: 2022-10-14
- Authors: Mukubwa, Grady Kathondo
- Date: 2022-10-14
- Subjects: Nanocapsules Design , Hydrogel , COVID-19 (Disease) , Characterization , Drug delivery systems
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/364955 , vital:65665
- Description: Covid-19 is a deadly viral disease that has been rampant around the world since 2019. Although the successful introduction of the vaccine has reduced the spread of covid-19, new cases and deaths are still being recorded. To date, no specific curative antiviral treatment has been approved for covid-19. However, many existing antiviral drugs have been and are still being studied against covid-19 and some of them, such as Remdesivir, have shown promise and could be repurposed to treat this infection. Unfortunately, antiviral drugs are prone to resistance as most of them have poor biopharmaceutical properties, including low solubility, permeability and bioavailability, which could hinder any clinical success. Recent advances in nanotechnology-based delivery systems have made it possible to improve the biopharmaceutical properties of many drugs, especially those of poorly water-soluble drugs, by formulating them as lipid nanoparticles (LNP). Thus, in order to contribute to the fight against covid-19, this work aimed to develop Lipid Nanocapsules (LNC), based on some natural raw materials, which could improve the biopharmaceutical properties of antiviral drugs. In addition, since covid-19 infection is mainly respiratory, this work also aimed to fabricate a targeted delivery system based on a hydrogel capable of entrapping LNC and ensuring their efficient deposition and release in the lungs. The LNC consisted of a mixture of medium-chain triglycerides oil (MCT oil), crude soy lecithin, tween 80, NaCl and water, while the hydrogel consisted of a chitosan-grafted-iota carrageenan-grafted-poly (acrylamide-co-acrylic acid) system (CS-iCar-p (AAm-Co-AA)). Efavirenz (EFV), a drug with very low water solubility that has recently been demonstrated to have the potential to influence sars-cov-2 life cycle through different targets (3CLP, RdRp, Hellicase, 3’to5’exonuclease, 2’-O-ribose methyltransferase and EndoRNAse), was chosen as the model drug to evaluate the developed delivery system. The combination of LNP and hydrogel results in a delivery system known as the LNP-hydrogel composite, an emerging area of research in the field of drug delivery. To date, no research has reported the design and fabrication of an LNC-CS-iCar-p (AAm-Co-AA) hydrogel composite that could effectively deliver an antiviral drug to the lungs in addition to its advantages in terms of biological activities. Prior to the design of experiment, EFV solubility was assessed in water, labrafac lipophile 1349 and MCT oil. After that, the Design Expert Software version 13 was used to design the different experiments performed in this work. The I-optimal mixture design of experiments was performed for both LNC preparation and CS-iCar-p (AAm-Co-AA) hydrogel synthesis to study the impact of raw materials on the characteristics of these delivery systems. LNC were prepared using the phase inversion method while the free radical precipitation graft copolymerization method was used to synthesize hydrogel. In order to build polynomial models that could predict the amount of drug both LNC and CS-iCar-p (AAm-Co-AA) hydrogel can entrap, a D-optimal (custom) randomized design was performed. Moreover, various characterization techniques were used to investigate the physicochemical properties of the developed delivery systems. Thereafter, drug release studies were performed using a 1% sodium lauryl sulfate solution adjusted to either pH 4 or 7. Solubility studies revealed that EFV was more soluble in labrafac lipophile 1349 and in MCT oil than in water; therefore, given its affordability, MCT oil was used for the LNC formulation. The design of experiment carried out allowed the construction of polynomial models that could predict, on the one hand, the droplet size, the polydispersity index and the Zeta potential of LNC, which were respectively around 50nm, below 0.2 and below -33. On the other hand, the model could predict the swelling capacity of the synthesized hydrogel, which was optimised to about 30,000% (300 g of water to 1 g of hydrogel). This turned out to be influenced by the proportion of polymers, the ratio of monomers as well as the concentration of the cross-linking agent. In addition, the characterization techniques further supported the improvement of EFV solubility by highlighting its conversion into its amorphous state after encapsulation in LNC. They also confirmed successful synthesis of CS-iCar-p (AAm-co-AA) hydrogel. LNC were able to encapsulate about 87% of EFV while the synthesized CS-iCar-p (AAm-co-AA) hydrogel entrapped around 53% of EFV encapsulated in LNC. While LNC were able to release 42% and 27% of EFV after 74 hours in a 1% sodium lauryl sulfate solution (SLS) at pH 7 and pH 4 respectively, the LNC-CS-iCar-p (AAm-co-AA) hydrogel composite released about 50% and 40% of the drug after 9 days in the same release medium. Interestingly, the chemical integrity of the drug was preserved throughout the manufacturing process up to after its release, suggesting that the developed LNC-CS-iCar-p (AAm-co-AA) hydrogel composite could be used as a novel potential anticovid-19 drugs delivery system. , Thesis (MSc) -- Faculty of Science, Chemistry, 2022
- Full Text:
- Date Issued: 2022-10-14
Synthesis, characterization and host-guest complexes of supramolecular assemblies based on calixarenes and cucurbiturils
- Authors: Baa, Ebenezer
- Date: 2022-10-14
- Subjects: Supramolecular chemistry , Calixarenes , Cucurbiturils , Metal-organic frameworks , Macrocyclic compounds , Drug delivery systems
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/365621 , vital:65765 , DOI https://doi.org/10.21504/10962/365621
- Description: The field of supramolecular chemistry has grown large and wide in both deepness of understanding, range of topics covered and scope and applications. Supramolecular self-assemblies are facilitated by a wide range of non-covalent intra and inter molecular interactions that range from hydrogen bonding to π-interaction and van der Waals. Macrocyclic compounds such as cucurbiturils and calixarenes have emerged as important classes of compounds with excellent potential of forming supramolecular assemblies. The porous nature of these compounds enables them to form host-guest supramolecular complexes stabilized by diverse range of non-covalent interactions. Furthermore, these compounds contain donor atoms capable of forming bonds with metal ions to yield metal complexes with interesting porous characteristics that deviate from their traditional hydrophobic cavity. The versatile nature of the resulting pores imply that they can accommodate diverse types of guests. This work explores the synthesis and characterization of a host of calixarenes and cucurbiturils. Self-assembly of these macrocycles with various metal ions results to the formation of porous metal organic framework (MOF) complexes. Four new calixarene typed compounds obtained from aromatic aldehydes and twenty-six cucurbituril metal complexes are reported. These macrocylces and their metal complexes also form supramolecular complexes with DMSO, methanol, isoniazid hydrochloride and ciprofloxacin hydrochlorides through either self-assembly, mechanochemistry and exposure to solvent vapors. The bulk materials have been characterized using nuclear magnetic resonance spectroscopy (NMR), Fourier transformed infrared spectroscopy (FTIR), powder and single crystal diffraction techniques and thermal studies thermogravimetric analysis (TGA) and differential thermal calorimetry (DSC). Data obtained from this study reveals that calixarenes can form supramolecular complexes with a frequently used laboratory solvents with BN22 showing appreciable selectivity for DMSO sorption from a solvent mixture. These compounds also form supramolecular complexes with drug molecules such as isoniazid and ciprofloxacin. Furthermore, the data reveals that choice of synthetic route of supramolecular ensembles dictates if the guest drug molecule will occupy the intrinsic or extrinsic pores of cucurbituril complexes. Biological studies on the obtained complexes reveal that the cucurbituril complexes are non-cytotoxic while the calixarenes show antibacterial activity against Escherichia coli and Staphylococcus aureus. Additionally, the study showed that ciprofloxacin can be successfully released from a calixarene host in a simulated body fluid although the host was also found to cross the dialysis membrane. The results of this study are important in that; - they can be exploited and developed in the selective sorption of certain guests and - that they can be used in the development of drug delivery systems that play a dual role of delivery and therapeutic activity. , Thesis (PhD) -- Faculty of Science, Chemistry, 2022
- Full Text:
- Date Issued: 2022-10-14
- Authors: Baa, Ebenezer
- Date: 2022-10-14
- Subjects: Supramolecular chemistry , Calixarenes , Cucurbiturils , Metal-organic frameworks , Macrocyclic compounds , Drug delivery systems
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/365621 , vital:65765 , DOI https://doi.org/10.21504/10962/365621
- Description: The field of supramolecular chemistry has grown large and wide in both deepness of understanding, range of topics covered and scope and applications. Supramolecular self-assemblies are facilitated by a wide range of non-covalent intra and inter molecular interactions that range from hydrogen bonding to π-interaction and van der Waals. Macrocyclic compounds such as cucurbiturils and calixarenes have emerged as important classes of compounds with excellent potential of forming supramolecular assemblies. The porous nature of these compounds enables them to form host-guest supramolecular complexes stabilized by diverse range of non-covalent interactions. Furthermore, these compounds contain donor atoms capable of forming bonds with metal ions to yield metal complexes with interesting porous characteristics that deviate from their traditional hydrophobic cavity. The versatile nature of the resulting pores imply that they can accommodate diverse types of guests. This work explores the synthesis and characterization of a host of calixarenes and cucurbiturils. Self-assembly of these macrocycles with various metal ions results to the formation of porous metal organic framework (MOF) complexes. Four new calixarene typed compounds obtained from aromatic aldehydes and twenty-six cucurbituril metal complexes are reported. These macrocylces and their metal complexes also form supramolecular complexes with DMSO, methanol, isoniazid hydrochloride and ciprofloxacin hydrochlorides through either self-assembly, mechanochemistry and exposure to solvent vapors. The bulk materials have been characterized using nuclear magnetic resonance spectroscopy (NMR), Fourier transformed infrared spectroscopy (FTIR), powder and single crystal diffraction techniques and thermal studies thermogravimetric analysis (TGA) and differential thermal calorimetry (DSC). Data obtained from this study reveals that calixarenes can form supramolecular complexes with a frequently used laboratory solvents with BN22 showing appreciable selectivity for DMSO sorption from a solvent mixture. These compounds also form supramolecular complexes with drug molecules such as isoniazid and ciprofloxacin. Furthermore, the data reveals that choice of synthetic route of supramolecular ensembles dictates if the guest drug molecule will occupy the intrinsic or extrinsic pores of cucurbituril complexes. Biological studies on the obtained complexes reveal that the cucurbituril complexes are non-cytotoxic while the calixarenes show antibacterial activity against Escherichia coli and Staphylococcus aureus. Additionally, the study showed that ciprofloxacin can be successfully released from a calixarene host in a simulated body fluid although the host was also found to cross the dialysis membrane. The results of this study are important in that; - they can be exploited and developed in the selective sorption of certain guests and - that they can be used in the development of drug delivery systems that play a dual role of delivery and therapeutic activity. , Thesis (PhD) -- Faculty of Science, Chemistry, 2022
- Full Text:
- Date Issued: 2022-10-14
Echogenic liposomes for ultrasound-triggered drug delivery
- Authors: Izuchukwu, Ezekiel Charles
- Date: 2021-10
- Subjects: Liposomes , Drug delivery systems , Colon (Anatomy) Cancer Treatment , Transmission electron microscopy , Fourier transform infrared spectroscopy , Liquid chromatography , Echogenic liposomes , Ultrasound-triggered drug delivery
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/188997 , vital:44805
- Description: Colorectal cancer is one of common cancers worldwide. It is the third most diagnosed cancer and the second leading cause of death. The use of 5-fluorouracil (5-FU) alone or in a chemotherapy regime has been the effective treatment of colorectal cancer patients. The efficacy of 5-FU in colorectal cancer treatment is significantly limited by drug resistance, gastrointestinal, and bone marrow toxicity through high-level expression of thymidylate synthase, justifying a need to improve its therapeutic index. Liposomes are colloidal membranes comprising of one or more lipid bilayers enclosing an aqueous core. They have been used to improve the therapeutic index of many anti-cancer drugs by changing drug absorption, elongating biological half-life, reducing metabolism, and reducing toxicity to healthy tissues. Echogenic liposomes are specifically designed to respond to external triggering like ultrasound stimulation by entrapping a gas or an emulsion that can vaporize. A liposome's unique property is that it can entrap both hydrophobic and hydrophilic substances simultaneously in the lipid bilayer and the aqueous core, respectively. These stimuli-responsive liposomes can be triggered externally with ultrasound, to release the chemotherapeutic cargo only at the required site. This research aims to formulate echogenic liposomes encapsulating 5-FU for potential ultrasound triggered release (echogenic). Liposome formulations wereprepared with lipid composition of crude soybean lecithin and cholesterol by thin-filmhydration method and the drug was passively loaded in the formulation. The 5-FU loadedliposomes were evaluated by dynamic light scattering (DLS) for particle size, polydispersityindex, and zeta potential and transmission electron microscopy (TEM) for morphology.Encapsulated liposomal formulations were also evaluated using physicochemical techniquesincluding thermogravimetric analysis (TGA), differential scanning calorimetry (DSC),Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Theencapsulation efficiency and release kinetics were studied using a validated high-performanceliquid chromatography (HPLC) method. Echogenic properties were explored by entrapping abiocompatible gas (argon) at the same time as the drug (5-FU) using a pressure/freezemethodology. The liposomal formulations were typically spherical with a size of about 150 nmand encapsulation efficiency of 62%. Low-frequency ultrasound (20 kHz) was used to triggerthe drug release from the complete formulation at 10%, 15%, and 20% amplitude and exposuretime of 5 min and 10 min. The rate of drug release from the nano-carrier was a function of theultrasound amplitude and exposure time and reached a maximum of 65% release under theconditions investigated. The cumulative release was investigated, with and without theapplication of ultrasound. It was demonstrated that the application of ultrasound resulted in complete release (99%) after 12 h while this dropped to 70% without ultrasound. These results are encouraging for optimizing ultrasound parameters for triggered and controlled release of the 5-FU, for conditions such as the management of cancer where low-power ultrasound can be applied. , Thesis (MSc) -- Faculty of Science, Chemistry, 2021
- Full Text:
- Date Issued: 2021-10
- Authors: Izuchukwu, Ezekiel Charles
- Date: 2021-10
- Subjects: Liposomes , Drug delivery systems , Colon (Anatomy) Cancer Treatment , Transmission electron microscopy , Fourier transform infrared spectroscopy , Liquid chromatography , Echogenic liposomes , Ultrasound-triggered drug delivery
- Language: English
- Type: Masters theses , text
- Identifier: http://hdl.handle.net/10962/188997 , vital:44805
- Description: Colorectal cancer is one of common cancers worldwide. It is the third most diagnosed cancer and the second leading cause of death. The use of 5-fluorouracil (5-FU) alone or in a chemotherapy regime has been the effective treatment of colorectal cancer patients. The efficacy of 5-FU in colorectal cancer treatment is significantly limited by drug resistance, gastrointestinal, and bone marrow toxicity through high-level expression of thymidylate synthase, justifying a need to improve its therapeutic index. Liposomes are colloidal membranes comprising of one or more lipid bilayers enclosing an aqueous core. They have been used to improve the therapeutic index of many anti-cancer drugs by changing drug absorption, elongating biological half-life, reducing metabolism, and reducing toxicity to healthy tissues. Echogenic liposomes are specifically designed to respond to external triggering like ultrasound stimulation by entrapping a gas or an emulsion that can vaporize. A liposome's unique property is that it can entrap both hydrophobic and hydrophilic substances simultaneously in the lipid bilayer and the aqueous core, respectively. These stimuli-responsive liposomes can be triggered externally with ultrasound, to release the chemotherapeutic cargo only at the required site. This research aims to formulate echogenic liposomes encapsulating 5-FU for potential ultrasound triggered release (echogenic). Liposome formulations wereprepared with lipid composition of crude soybean lecithin and cholesterol by thin-filmhydration method and the drug was passively loaded in the formulation. The 5-FU loadedliposomes were evaluated by dynamic light scattering (DLS) for particle size, polydispersityindex, and zeta potential and transmission electron microscopy (TEM) for morphology.Encapsulated liposomal formulations were also evaluated using physicochemical techniquesincluding thermogravimetric analysis (TGA), differential scanning calorimetry (DSC),Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Theencapsulation efficiency and release kinetics were studied using a validated high-performanceliquid chromatography (HPLC) method. Echogenic properties were explored by entrapping abiocompatible gas (argon) at the same time as the drug (5-FU) using a pressure/freezemethodology. The liposomal formulations were typically spherical with a size of about 150 nmand encapsulation efficiency of 62%. Low-frequency ultrasound (20 kHz) was used to triggerthe drug release from the complete formulation at 10%, 15%, and 20% amplitude and exposuretime of 5 min and 10 min. The rate of drug release from the nano-carrier was a function of theultrasound amplitude and exposure time and reached a maximum of 65% release under theconditions investigated. The cumulative release was investigated, with and without theapplication of ultrasound. It was demonstrated that the application of ultrasound resulted in complete release (99%) after 12 h while this dropped to 70% without ultrasound. These results are encouraging for optimizing ultrasound parameters for triggered and controlled release of the 5-FU, for conditions such as the management of cancer where low-power ultrasound can be applied. , Thesis (MSc) -- Faculty of Science, Chemistry, 2021
- Full Text:
- Date Issued: 2021-10
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
- «
- ‹
- 1
- ›
- »