| Publication Type |
dissertation |
| School or College |
College of Pharmacy |
| Department |
Pharmaceutics & Pharmaceutical Chemistry |
| Author |
Kim, Dongin |
| Title |
pH-Sensitive Micelle for multidrug resistant tumors |
| Date |
2010-05-14 |
| Description |
The goal of this hypothesis-driven application is to develop a polymeric micelle that targets multidrug resistant (MDR) tumors via pH sensitivity. The micelles target tumors that overexpressed folate receptors on their surface, and internalized into the tumor cells by folate receptor-mediated endocytosis. They also evade P-glycoprotein pumps on the surface of MDR tumors. After cellular internalization, the micelles release the encapsulated drug (doxorubicin: DOX) in response to pH changes (extracellular tumor pH -7.0 or endosomal pH -6.0). Concurrent with the release of the drug, the endosomal membrane disruption by polyhistidine prevents other resistance mechanisms, including drug sequestration and endosome recycling (exocytosis). Two generations of pH-sensitive micelles have been developed and tested. The first generation expected to be sensitive at the extracellular tumor pH (-7.0) involved a poly(L-histidine) (MW: 5K) (polyHis) core. The second generation composed of a poly(histidine(His)-co-phenylalanine(Phe)) (poly(His-co-Phe)) (MW: 5K) core is expected to be sensitive at the endosomal pH (-6.0) due to the increased hydrophobicity of phenylalanine compared with histidine. Both micelles use PEG (MW: 2K) strands as hydrophilic shell. To adjust the micelle pH sensitivity at pH 7.0 or pH 6.0, a mixed micelle formulation method was utilized by adding poly(L-lactide) (MW: 3K)-/?-PEG (MW: 2K) with a folate receptor (FR) ligand attached (PLLA-b-PEG-folate). DOX was loaded into both the mixed micelle formulations (polyHis-b-PEG/PLLA-b- PEG-folate (80/20 wt/wt%) and poly(His-co-Phe)-£-PEG/PLLA-£-PEG-folate (80/20 wt/wt%)) using the conventional dialysis method. Both DOX-loaded micelles had a particle size distribution ~ 100 nm and stable at pH 8.0 (micelle formulation pH) and 7.4 (physiological blood pH), but destabilized at pH 7.0 or at pH 6.0. Their pH sensitivity was confirmed by changes in particle size, transmittance, and critical micelle concentration, illustrating drug release at lower pHs. In vitro cellular experiments and in vivo studies demonstrated the feasibility of pH-sensitive micelles, and confirmed the advantages of pH-sensitive micelles over pH-insensitive micelles (PLLA-b-PEG/PLLA- 6-PEG-folate (80/20 wt/wt%)) or the free drug (DOX). In summary, poly(L-histidine)-based pH-sensitive micelles have great potential as a tumor-killing platform. However, more investigations into future clinical applications are needed because of the heterogeneous nature of biological tumors and tumor stem cells. |
| Type |
Text |
| Publisher |
University of Utah |
| Subject |
Micelles; Cancer; Multidrug Resistance |
| Subject MESH |
Micelles; Neoplasms; Drug Resistance, Multiple |
| Dissertation Institution |
University of Utah |
| Dissertation Name |
PhD |
| Language |
eng |
| Relation is Version of |
Digital reproduction of "pH-sensitive micelle for multidrug resistant tumors." Spencer S. Eccles Health Sciences Library. Print version of "pH-sensitive micelle for multidrug resistant tumors." available at J. Willard Marriot Library Special Collection. RM31.5 2009.K56. |
| Rights Management |
© Dongin Kim |
| Format Medium |
application/pdf |
| Format Extent |
3,009,433 bytes |
| Source |
Original: University of Utah Spencer S. Eccles Health Sciences Library |
| Conversion Specifications |
Original scanned on Fujitsi fi-5220G as 400 dpi to pdf using ABBYY FineReader 10 |
| ARK |
ark:/87278/s6rn3pjg |
| Setname |
ir_etd |
| ID |
194190 |
| Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6rn3pjg |
