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The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer
Dissertation (MSc)--University of Pretoria, 2010.
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| Format: | Thesis |
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University of Pretoria
2013
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| _version_ | 1867613725099294720 |
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| access_status_str | Open Access |
| author2 | Medlen, Connie E. |
| author_browse | Medlen, Connie E. |
| author_facet | Medlen, Connie E. |
| collection | Thesis |
| dc_rights_str_mv | © 2009, University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Dissertation (MSc)--University of Pretoria, 2010. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/24589 |
| institution | University of Pretoria (South Africa) |
| last_indexed | 2026-06-10T12:40:42.021Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2013 |
| publishDateRange | 2013 |
| publishDateSort | 2013 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/24589 The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer Medlen, Connie E. Cromarty, Allan Duncan sharfuddin.sayed@gmail.com Sayed, Sharfuddin Sakil Methotrexate Anti-cancer Nude mice Pharmacokinetics Carrageenan inflammation model D85 Anti-inflammatory UCTD Dissertation (MSc)--University of Pretoria, 2010. A major effort to develop anticancer drugs through both empiric screening and rational design of new compounds has been under way for over 30 years (Katzung, 2004). In recent years, research and development in the field of sitespecific drug therapy has progressed significantly. Safe and non-toxic formulations of cytotoxic drugs based on polymers with their improved sitespecific delivery and effective activation to biologically active cytotoxic compounds at the targeted tumours have become a promising approach to cancer therapy. Drug delivery systems based on polymer micelles, coated microand nanoparticles, liposomes and various pro-drug systems including watersoluble polymer–drug conjugates and immunoconjugates have been prepared and extensively studied as novel drug delivery systems designed for cancer chemotherapy. Amongst these drug delivery systems that enable specific drug delivery and release, water-soluble polymer–drug conjugates rank among the most promising, versatile and efficient systems. This dissertation reviews the preclinical testing and pharmacokinetic study of D85, a novel water-soluble macromolecular pro-drug that is a polymer with pHcontrolled methotrexate (MTX) release with potential for treatment of cancer in humans (Ulbrich&Subr, 2004). As MTX is also indicated in low doses for the treatment of chronic inflammatory conditions, the polymer was further tested in an acute inflammatory model to determine whether the polymer would be more effective than MTX in controlling inflammation. The objective of this study was to compare the potency and efficacy of D85 to MTX. D85, a MTX conjugated polymeric lead compound, was designed and synthesised as a potential anti-neoplastic and anti-inflammatory agent. It was initially tested in vitro on three different cancer cell lines where selective toxicity towards the cancer cell cultures compared to primary cell cultures and greater toxicity than MTX was observed. The initial in vitro tests showed very promising results with D85 demonstrating approximately 300 times greater cytotoxicity than MTX against a colon cancer cell line (COLO 320 DM). This high cytotoxic effect warranted further investigation in an in vivo colon cancer tumour model. An induced murine tumour model of COLO 320 DM was successfully developed in nude mice, and the anti-tumour efficacy of D85 tested in this model. The maximum tolerated dose of D85 was established by carrying out an in vivo dose ranging toxicity test in BALB/c mice. The anti-inflammatory effects of D85 were also determined using the carrageenan-induced paw oedema model in rats where carrageenan was injected into a footpad of a rat causing acute oedema, which was measured using a water displacement plethysmometer. D85 was found to exacerbate the inflammatory response. Finally, the pharmacokinetic parameters of MTX and D85 were assessed using a LC/MS/MS method specifically developed and validated to determine low concentrations of MTX in small volumes of plasma. This new method made use of online solid phase extraction and sample cleanup on 2μl injections of diluted plasma allowing an entire pharmacokinetics study to be completed on an individual rat. Fairly similar pharmacokinetics were determined from both compounds. Copyright Pharmacology unrestricted 2013-09-06T18:02:17Z 2010-05-12 2013-09-06T18:02:17Z 2010-04-16 2010-05-12 2010-05-12 Dissertation Sayed, SS 2009, The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer, MSc dissertation, University of Pretoria, Pretoria, viewed yymmdd < http://hdl.handle.net/2263/24589 > E10/247/gm http://hdl.handle.net/2263/24589 http://upetd.up.ac.za/thesis/available/etd-05122010-154612/ © 2009, University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | Methotrexate Anti-cancer Nude mice Pharmacokinetics Carrageenan inflammation model D85 Anti-inflammatory UCTD The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title | The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title_full | The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title_fullStr | The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title_full_unstemmed | The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title_short | The toxicity, pharmacokinetics, anti-inflammatory and anti-tumour properties of a methotrexate polymer |
| title_sort | toxicity pharmacokinetics anti inflammatory and anti tumour properties of a methotrexate polymer |
| topic | Methotrexate Anti-cancer Nude mice Pharmacokinetics Carrageenan inflammation model D85 Anti-inflammatory UCTD |
| url | http://hdl.handle.net/2263/24589 http://upetd.up.ac.za/thesis/available/etd-05122010-154612/ |