Biodegradable polymer micro- and nanoparticles as protein delivery systems : influence of microparticle morphology and improvement of protein loading capacity of nanoparticles
In this work, microparticles and nanoparticles were investigated as protein delivery system. Chapter 1 firstly describes development and current status of degradable polymer microspheres as protein delivery systems.In Chapter 2 with the aim to establish the relationship of particles morphology, drug...
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| Format: | Dissertation |
| Sprache: | Englisch |
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Philipps-Universität Marburg
2007
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| Zusammenfassung: | In this work, microparticles and nanoparticles were investigated as protein delivery system. Chapter 1 firstly describes development and current status of degradable polymer microspheres as protein delivery systems.In Chapter 2 with the aim to establish the relationship of particles morphology, drug distribution and release profiles based on different polymer properties, relatively hydrophobic and hydrophilic PLGAs with different end functional groups were selected to prepare microspheres using W/O/W method with different porosity, pore size and drug loading. The results showed that morphology of particles play a different role in the release process depending on the property of polymer. For relative hydrophilic polymer, as RG503H, morphology influenced the burst release to the less extent relative to hydrophobic polymer RG502. Vice verse, at the slow release stage, morphology showed much less pronounced influence for hydrophobic polymer RG502. In Chapter 3 with the purpose to achieve high protein loading and to improve the release profiles, we supposed that protein can be effectively absorbed onto charged nanoparticles and can be released in the controlled manner. PLGA and PSS polymer blend were used to mimic negatively charged polymer and to prepare charged nanoparticles with variable surface charge density through adjusting the ratio of PSS to PLGA. Increased PSS led to the increment of size and high charge density of nanoparticles. Adsorption isotherm showed higher affinity of protein to the nanoparticles with increased PSS. Loading capacity of lysozyme closely related to charge density of nanoparticles. Adsorption process of protein and loading capacity investigations suggest that the electrostatic forces dominate the interaction between proteins and nanoparticles. Bioactivity determination showed protein remains intact during whole process and the release profiles were dependent on protein loading. This study proves our hypothesis that it is a feasible and mild method using charged nanoparticles to effectively load oppositely charged protein with full bioactivity. In Chapter 4 due to the fast release and location of protein on the surface of nanoparticles prepared in chapter 3, a layer-by-layer nanostructure was assumed to fulfill these requirements. Using chitosan and its derivatives as coating materials with potential functional application like mucoadhesivity, penetration enhancement, layer-by-layer nanocarriers through deposition of polymer on the surface of protein loaded nanoparticles were investigated. Increased size and inversion of zeta-potential of particles, as well as TEM observations evidenced the coating of chitosan on the surface. Due to the stronger electrostatic interaction between chitosan and nanoparticles, dissociation of lysozyme was observed. Dissociation of lysozyme was dependent on polymer composite, irrespective of initial protein loading. Moreover, with this polymer coating more stable particles were detected in PBS, without initial release within 24 hours. This study showed the feasibility of designing a layer-by-layer protein nanocarrier with polymer coating on the surface of protein loaded nanoparticles to further improve the stability and release profiles of protein. In Chapter 5 based on the promising results of chapter 3, same strategies including nanoparticles preparation and protein loading method were employed using negatively charged polymer SB-PVA-PLGA and P(VS-VA)-PLGA. Stable nanoparticles suspension with narrow size distribution, and high reproducibility was obtained with polymer SB-PVA-PLGA. Based on equal sulfonic substitution, longer PLGA chain length of P(VS-VA)-PLGA demonstrated better nanoparticles properties as narrow size and single peak zeta-potential distribution than shorter PLGA chain length polymer. Increased sulfonic substitution degree of P(VS-VA)-PLGA decreased the size linearly, however, no significant difference in zeta-potential was observed. SB-PVA-PLGA showed higher loading capacity as 77 µg/mg relative to this new class polymer P(VS-VA)-PLGA. Additionally, higher sulfonic substitution degree resulted in higher loading capacity. Whereas, lower loading capacity of lysozyme was observed for polymer with longer PLGA chain length, indicating that the balance of charge density and hydrophilic property is necessary for this protein adsorption process. |
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| Umfang: | 161 Seiten |
| DOI: | 10.17192/z2007.0537 |