Design, Synthesis and Study of Novel Multivalent Ligands - Toward New Markers of Cancer Cells

Cancer is lacking early detection methods and treatment specificity. In order to increase the sensitivity and specificity towards cancer cells, we propose the use of multivalent interactions targeting specific receptor combinations at the cancer cell surface. In this thesis, we explored the design of multimers, which could provide such interactions. The design was investigated and revisited based on specific parameters, essential for the creation of multivalent interactions such as thermodynamics. The synthesis was designed so that libraries of homo- and hetero-multimers of different valencies can be obtained efficiently with good yields. The established synthetic scheme is empowered by its modularity, necessary to investigate different essential factors. Trimers composed of micromolar affinity MSH(4) targeting the MC1-R, overexpressed in melanoma, were investigated on a model cell line and resulted in the creation of nanomolar affinity constructs with up to 350 fold increase in affinity. Different multimers such as hexavalent and nonavalent dendrimers were synthesized and studied for their properties. All constructs had nanomolar affinity and showed to be non-toxic up to micromolar concentrations and imaging studies also confirmed their internalization, which overall demonstrate the potential for these compounds to be used as markers for cancer cells and as delivery agents. Trimers targeting the CCK2-R were similarly investigated for their potential as pancreatic cancer markers. However, those constructs did not seem to result in the expected enhancements in affinity, but the affinity of the initial monovalent agonist was in the 10-50 nanomolar range. As we were unable to design micromolar affinity agonist we investigated the use of antagonists. This study, revealed the importance of thermodynamics in the creation of multivalent interaction. Heterotrivalent ligands (CCK and MSH) were investigated for their potential in cross-linking different receptors and the study demonstrated the subtility to detect cross-linking. Finally, the different attempts toward the efficient synthesis of a tetra-orthogonal scaffold, a key feature needed to generate multimers that could target up to 3 different receptors was investigated and showed promising results. It is our hypothesis that such an approach will ultimately lead to specific markers of tumor cells, which could be used as diagnosis agents when modified with an imaging moiety and as a therapeutic agent when modified with a drug.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Graduate College

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2012

Author dc:creator

• Brabez, Nabila

Advisor dc:contributor.advisor

• Hruby, Victor J.

Committee members dc:contributor.committeemember

• Ghosh, Indraneel
• Mash, Eugene A.
• Meuillet, Emmanuelle
• Hruby, Victor J.
• Lynch, Ronald M.

• multivalent interactions
• peptide dendrimers
• scaffold
• targeted therapy
• Chemistry
• cancer
• GPCR

Statement dc:rights

• Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10150/238691

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/238691