A study of alternative delivery strategies and systems to enhance the therapeutic effect and cytotoxic activity of anticancer agents.
Published: 2005
Language: eng
Number of pages: 256
Description: The efficacy of traditional cancer chemotherapy is limited by many factors including drug toxicity to normal tissue, drug levels achievable in solid tumors, and the development of drug resistance. This thesis details the development and investigation of microspheres (MS) for the loco-regional delivery of anticancer drugs, mitomycin C (MMC) and doxorubicin (Dox), to enhance traditional chemotherapy.An in vivo study of intratumorally administered MMC-Ox-MS was performed to investigate its therapeutic effect on mice bearing EMT6 solid tumors. A 79% delay in tumor growth was observed in mice receiving intratumoral (1T) injections of MMC-Ox-MS compared to controls. A 185% delay was attained when MMC-Ox-MS and Dox-MS were co-administered. No signs of general toxicity were observed in the groups receiving IT treatment.Sulfopropyl dextran MS were modified by oxidation (Ox-MS) to enhance MMC loading and provide sustained MMC release. The released drug was found to maintain its bioactivity against cancer cells.Taken together, the results from this series of studies demonstrates that Ox-MS can be an effective carrier for MMC, that in vitro-in vivo correlation models can be developed to predict in vivo drug release, that the IT route has the potential to advance solid tumor treatment by localizing drug effects to the target tissue, and that the combination of MMC and Dox may improve cancer chemotherapy by providing synergistic toxic effects to tumor cells.Drug release from MS in vitro can markedly differ from drug release in vivo. A method was designed to study Dox release from Dox-loaded MS (Dox-MS) in vivo. In vitro systems were also developed and investigated for their ability to correlate in vitro with in vivo drug release. Three of the developed systems generated release profiles that were highly correlated with in vivo release (r2 > 0.9). These systems have the potential to predict the in vivo performance of locally administered MS.In vitro investigations of various MMC/Dox combinations were conducted to study their effectiveness as a combination. It was found that greater-than-additive cytotoxicity can be attained when MMC and Dox are administered simultaneously, or Dox precedes MMC.
Notes: Advisor: Wu, Shirley

Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 3078.