| Publication Type |
dissertation |
| School or College |
College of Pharmacy |
| Department |
Pharmaceutics & Pharmaceutical Chemistry |
| Author |
Bikram, Malavosklish |
| Title |
Biodegradable multiblock copolymers for gene delivery |
| Date |
2005-05 |
| Description |
Nonviral gene delivery has developed into a promising alternative to viral gene delivery and has the potential to correct many genetic disorders as well as to treat acquired diseases. However, the cytotoxicities related to the high charge densities of effective high molecular weight cationic polymers represent a major hurdle to the development of gene delivery systems that limits their clinical applicability. Thus, the purpose of this research was to develop biodegradable high molecular weight multiblock copolymers (MBC). The polymers consist of repeating blocks of low molecular weight poly(ethylene glycol) (PEG) and poly(L-lysine) (PLL). PLL was used as the DNA condensing agent and PEG was used to provide steric stabilization of the polymer/pDNA complexes as well as to introduce the biodegradable ester bonds onto the backbone of the MBC. The histidine derivative, JV, JV-dimethylhistidine, was conjugated at various mol % to the primary e-amines of PLL to produce the final PEG-PLL-g-NHis MBC, for endosomal buffering. The first section of this dissertation deals with synthesis and characterization of the conjugates PEG-PLL-g-5 % NHis, PEG-PLL-g-9 % NHis, PEG-PLL-g-16 % NHis, and PEG-PLL-g-22 % NHis MBC. The results showed that the 16 % conjugated MBC produced the highest transfection efficiency with the least cytotoxicity as compared to PLL 25000. Characterization of this optimized conjugate showed that the pK of the imidazole ring was ~4.75 and the polymer degradation half-life (ti/2) was ~5 h in buffer. Thus, the MBC were shown to be effective and biocompatible polymers for gene delivery. The second half of the research deals with degradation studies of the MBC and biodistribution in mice. The results showed that there was no significant degradation at low pH, decreased polymer t\a in 10 % mouse serum of ~2 h, and polymer degradation within complexes occurred between 4-8 h in 10 % mouse serum. Biodistribution data revealed that the complexes are able to circulate in the blood for up to 3 d, which was reflected in the various organs. The data suggest that PEG was able to provide steric stabilization by promoting the favorable binding of dysopsonins that prevent uptake by the reticuloendothelial system (RES). |
| Type |
Text |
| Publisher |
University of Utah |
| Subject |
Polymeric drug delivery systems; Gene therapy; Block copolymers |
| Subject MESH |
Gene Therapy; Drugs, Investigational; Polymers; Pharmaceutical Preparations |
| Dissertation Institution |
University of Utah |
| Dissertation Name |
PhD |
| Language |
eng |
| Relation is Version of |
Digital reproduction of "Biodegradable multiblock copolymers for gene delivery". Spencer S. Eccles Health Sciences Library. |
| Rights Management |
© Malavosklish Bikram. |
| Format Medium |
application/pdf |
| Format Extent |
3,821,022 bytes |
| Source |
Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available) |
| Master File Extent |
3,821,098 bytes |
| ARK |
ark:/87278/s6bz67w3 |
| Setname |
ir_etd |
| ID |
191502 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6bz67w3 |
