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

Author

Cassandra Dill, Chapman UniversityFollow

Date of Award

Fall 1-2021

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Kamaljit Kaur, PhD.

Second Advisor

Sun Yang, B.S. Pharmacy, Ph.D.

Third Advisor

Aftab Ahmed, Ph.D.

Abstract

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 in vitro melanoma cell studies were conducted. Overall, KK-11b stability was constant, remaining present in serum-free cell media, water, and preliminary in vitro 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 in vivo murine studies if results remain promising.

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Recommended Citation

Dill, C. L. The Development of a Cancer-Targeting Peptide-Drug Conjugate for the Treatment of Melanoma. [master’s thesis]. Irvine, CA: Chapman University. https://doi.org/10.36837/chapman.000201