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UBC Theses and Dissertations
Development and evaluation of radiolabeled macromolecular conjugates for targeted delivery of anti-arthritic drugs Nosrati, Zeynab
Abstract
Many Rheumatoid arthritis (RA) patients fail to respond satisfactorily to frequently given anti-arthritic drugs or experience side effects. The main reason for sub-optimal treatment is that insufficient drug doses reach the joints, therefore higher and more frequent doses are needed. To improve drug pharmacological profile and direct the anti-inflammatory activity to the inflamed joints, a macromolecular prodrug was synthesized to deliver more of the drug specifically to inflamed joints, to maintain appropriate drug concentration thereafter, and to avoid side effects in other organs. The methods encompass the chemical syntheses of the polymeric prodrugs and the investigation of their stability and release kinetics. The pharmacokinetics of the prodrug was established after radiolabeling with ¹¹¹In, and preclinical SPECT/CT imaging in an RA mouse model. The efficacy of the prodrugs was also established in the same RA model and compared to the free drug given in the same timing as it is currently administered to patients. Delivering methotrexate (MTX) bound to a folic acid-modified polymeric carrier produced a significant increase in drug uptake in the inflamed joints. When MTX was delivered as a prodrug, a 2 to 4 times lower dose given every two weeks was just as effective as two standard dosages per week of free MTX. The work presented in this thesis also explores the application of infrared thermal imaging (IRT) in longitudinal preclinical setting to monitor arthritis onset, disease activity and therapeutic efficacies. A standardized easy to use protocol was developed to utilize IRT for reliable detection of temperature differences in the joint tissues of RA animals. IRT successfully validated the arthritis induced mice and selected those which mimic human RA the most to be used in preclinical testing of a novel drug delivery system. The findings from this study suggest that IRT can be used as a better tool than caliper measurements for rapid, non-invasive and unbiased quantification of a new drug’s pharmacological effect.
Item Metadata
| Title |
Development and evaluation of radiolabeled macromolecular conjugates for targeted delivery of anti-arthritic drugs
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| Creator | |
| Supervisor | |
| Publisher |
University of British Columbia
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| Date Issued |
2021
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| Description |
Many Rheumatoid arthritis (RA) patients fail to respond satisfactorily to frequently given anti-arthritic drugs or experience side effects. The main reason for sub-optimal treatment is that insufficient drug doses reach the joints, therefore higher and more frequent doses are needed. To improve drug pharmacological profile and direct the anti-inflammatory activity to the inflamed joints, a macromolecular prodrug was synthesized to deliver more of the drug specifically to inflamed joints, to maintain appropriate drug concentration thereafter, and to avoid side effects in other organs.
The methods encompass the chemical syntheses of the polymeric prodrugs and the investigation of their stability and release kinetics. The pharmacokinetics of the prodrug was established after radiolabeling with ¹¹¹In, and preclinical SPECT/CT imaging in an RA mouse model. The efficacy of the prodrugs was also established in the same RA model and compared to the free drug given in the same timing as it is currently administered to patients. Delivering methotrexate (MTX) bound to a folic acid-modified polymeric carrier produced a significant increase in drug uptake in the inflamed joints. When MTX was delivered as a prodrug, a 2 to 4 times lower dose given every two weeks was just as effective as two standard dosages per week of free MTX.
The work presented in this thesis also explores the application of infrared thermal imaging (IRT) in longitudinal preclinical setting to monitor arthritis onset, disease activity and therapeutic efficacies. A standardized easy to use protocol was developed to utilize IRT for reliable detection of temperature differences in the joint tissues of RA animals. IRT successfully validated the arthritis induced mice and selected those which mimic human RA the most to be used in preclinical testing of a novel drug delivery system. The findings from this study suggest that IRT can be used as a better tool than caliper measurements for rapid, non-invasive and unbiased quantification of a new drug’s pharmacological effect.
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| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2025-01-31
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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| DOI |
10.14288/1.0398492
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| URI | |
| Degree | |
| Program | |
| Affiliation | |
| Degree Grantor |
University of British Columbia
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| Graduation Date |
2021-11
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| Campus | |
| Scholarly Level |
Graduate
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Attribution-NonCommercial-NoDerivatives 4.0 International