Usage
  • 78 views
  • 45 downloads

Targeted Delivery of Arsenic Compounds to Tumor Cells Using Polymeric Micelles

  • Author / Creator
    Zhang, Qi
  • Arsenic trioxide (ATO), dissolved in water as arsenous acid or inorganic arsenite (AsIII), is an effective chemotherapeutic agent against acute promyelocytic leukemia (APL). It has been investigated as a potential treatment for a variety of solid tumors although with much poorer efficacy than for APL. The toxicity of AsIII and its derivatives has limited its use. Nano drug delivery systems such as polymeric micelles with the capability to deliver the drug into targeted tumor areas are expected to improve the therapeutic efficacy of arsenic therapy for solid tumor treatment and alleviate its adverse side effects. The ultimate goal of this study is to develop a polymeric micelle system for targeted delivery of arsenicals to specific tumor cells. Towards this goal, a strategy involving thiol functionalization of polymer chains was developed to effectively encapsulate trivalent arsenic compounds into polymeric micelles. The mercaptohexylamino group was conjugated to methoxy poly(ethylene oxide)-block-poly(α-carboxylate--caprolactone) (PEO-b-PCCL) via an amide bond, forming thiolated methoxy poly(ethylene oxide)-block-poly[α-(6-mercaptohexyl amino)carboxylate--caprolactone] [PEO-b-P(CCLC6-SH)]. A higher arsenic loading content was achieved with thiolated micelles compared to micelles without thiol groups in the micelle core. The weight percentage of encapsulated arsenic element in the micelles was in the range of 2.5 ~ 4.0 wt% depending on the total thiol amount in the micelles, which corresponded with ~ 0.65 mole of arsenic per mole of thiol groups. The formation of the As‒S bond in the micelle core slowed down the arsenic release from the micelles. The arsenic release could be triggered by addition of thiol-containing small molecules such as glutathione (GSH), which compete with polymer chains for arsenic binding. Mixed micelles formed from a mixture of PEO-b-PCCL and PEO-b-P(CCLC6-SH) polymers with surface modification of affinity ligands, i.e. RGD-containing peptides, were prepared to facilitate the targeted delivery of arsenic to targeting tumor cells. Although the peptide modification enhanced the cytotoxicity and cellular uptake of arsenic encapsulated in mixed micelles, the high arsenic burst release (~50% of initially encapsulated AsIII) from mixed micelles diminished the targeting activity of affinity ligands, and peptide-decorated mixed micelles did not exhibit superior targeting performance than non-mixed micelles or free AsIII. The arsenic burst release can be reduced by enhancing the micelle stability. Mixed micelles formed from a mixture of PEO-b-PBCL and PEO-b-P(CCLC6-SH) and terpolymeric micelles formed from PEO-b-P(CCLC6-SH)-b-PCL both had reduced AsIII burst release (~ 20% of initially encapsulated AsIII). The incorporation of the PCL block into the PEO-b-P(CCLC6-SH) polymer not only enhanced the micelle stability, but also added extra complexity to the micelle structure. The chain arrangement of the polyester block influenced the micelle surface charge by affecting the micelle structure, which further affected the cellular uptake of encapsulated arsenic. The results revealed in this thesis demonstrate that polymeric micelles are a versatile carrier with great tunable properties and have great potential for the successful targeted delivery of arsenic chemotherapeutic agents to solid tumors.

  • Subjects / Keywords
  • Graduation date
    2016-06:Fall 2016
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3Z31P03P
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medical Sciences-Laboratory Medicine and Pathology
  • Specialization
    • Laboratory Medicine and Pathology
  • Supervisor / co-supervisor and their department(s)
    • Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Le, Xiao-Chun Chris (Department of Laboratory Medicine and Pathology)
  • Examining committee members and their departments
    • Loebenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Weinfeld, Michael (Department of Oncology)
    • Li, Xing-Fang (Department of Laboratory Medicine and Pathology)
    • Keelan, Monika (Department of Laboratory Medicine and Pathology)
    • Mester, Zoltan (National Research Council)