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Permanent link (DOI): https://doi.org/10.7939/R3Z31P03P

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Targeted Delivery of Arsenic Compounds to Tumor Cells Using Polymeric Micelles Open Access

Descriptions

Other title
Subject/Keyword
Drug delivery
Arsenic
Polymeric micelle
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Zhang, Qi
Supervisor and department
Le, Xiao-Chun Chris (Department of Laboratory Medicine and Pathology)
Lavasanifar, Afsaneh (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Keelan, Monika (Department of Laboratory Medicine and Pathology)
Mester, Zoltan (National Research Council)
Loebenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences)
Li, Xing-Fang (Department of Laboratory Medicine and Pathology)
Weinfeld, Michael (Department of Oncology)
Department
Medical Sciences-Laboratory Medicine and Pathology
Specialization
Laboratory Medicine and Pathology
Date accepted
2016-07-08T14:07:23Z
Graduation date
2016-06:Fall 2016
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3Z31P03P
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication
Chen BB, Liu QQ, Popowich A, Shen SW, Yan XW, Zhang Q, et al. 2015. Therapeutic and analytical applications of arsenic binding to proteins. Metallomics 7:39-55.Zhang Q, Vakili MR, Li XF, Lavasanifar A, Le XC. 2014. Polymeric micelles for gsh-triggered delivery of arsenic species to cancer cells. Biomaterials 35:7088-7100.

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