Design, Synthesis and Development of Transporter Targeting Agents For Image-Guided Therapy and Drug Delivery

<p>The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. <em>In vitro</em> stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular ^99mTc-N4amG and ^99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed ^99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of^99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that ^99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested <em>in vivo</em> using tumor-bearing animal models. ^99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both ^99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of ^99mTc-N4amG was correlated with Ki-67 expression. Both ^99mTc-N4amG and ^99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, ⁶⁸Ga-GP was compared to ¹⁸F-FDG in rabbit PET imaging studies. ⁶⁸Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with ¹⁸F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in <em>in vitro</em> cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in <em>in vivo</em> tumor growth delay study.<strong> </strong>In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Tsao, Ning

Contributors dc:contributor

• David J. Yang, Ph.D.
• Franklin C. Wong, M.D., Ph.D., J.D.
• Edward Jackson, Ph.D.

• glycopeptide
• Imaging probe
• PET imaging
• SPECT imaging
• guanine
• theranostics
• drug delivery system
• Amino Acids, Peptides, and Proteins
• Diagnosis
• Heterocyclic Compounds
• Medicinal Chemistry and Pharmaceutics
• Medicine and Health Sciences
• Nucleic Acids, Nucleotides, and Nucleosides
• Other Analytical, Diagnostic and Therapeutic Techniques and Equipment
• Pharmacology
• Radiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/350

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1385