The Development of a Cancer-Targeting Peptide-Drug Conjugate for the Treatment of Melanoma

<p>Cancer is an ongoing global pandemic which has caused a dramatic shift in research priorities. One of the most aggressive and difficult to treat has invariably remained metastatic melanoma. Although encompassing only 4% of overall skin cancer diagnoses, chances for recovery were slim until recent revolutionary development of immunotherapy adding to its regimen spectrum. This is due to its resistance to many standard-of-care treatment methods, along with its relatively high-metastatic potential. Within the past decade, eight new targeted and immune checkpoint inhibitors have gained FDA approval. The median life survival has increased significantly from 9 months to over 2 years as a result of this concerted drug development effort; however, this rapid development of treatment technologies come with new severe adverse effects, as well as increased opportunity for toxicity and drug resistance. It is not uncommon for a treatment to switch before originally projected due to lack of patient therapeutic response to a typical cytotoxic drug. One novel method to avoid this effect is use of a peptide delivery system, essentially increasing its targeted delivery. In this thesis, a ligand, dubbed KK-11b (sequence: CVPWxEPAYQrFL), synthetically made to form a cell-specific, noncytotoxic 13-mer peptide residue, is conjugated to a linker, sulfo-SMCC, and chemotherapeutic drug doxorubicin. Together, these form a new family of targeted drug therapies: peptide-drug conjugates (PDCs). The development and characterization are discussed, its stability analyzed, and, finally, preliminary <em>in vitro</em> melanoma cell studies were conducted. Overall, KK-11b stability was constant, remaining present in serum-free cell media, water, and preliminary <em>in vitro</em> A375 melanoma cell studies. More analysis will be conducted to test the cytotoxicity of KK-11 conjugate in alternate types of melanoma cells, as well as in the presence of human serum, before ultimately progressing to <em>in vivo</em> murine studies if results remain promising.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2021

Author dc:creator

• Dill, Cassandra

Contributors dc:contributor

• Kamaljit Kaur, PhD.
• Sun Yang, B.S. Pharmacy, Ph.D.
• Aftab Ahmed, Ph.D.

• peptide-drug conjugate
• melanoma
• Medicinal and Pharmaceutical Chemistry
• Other Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/14

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_theses-1014