Synthesis and Characterization of Hybrid Peptide Prodrugs for Combination Therapy

• Main Author: Perez, Tanner James
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2023
• Subjects: Biochemistry; Chemistry; Oncology; Pharmaceutical sciences
• ISBN: 9798381730111

Combination therapy, where two or more therapeutic agents are combined to target different cellular pathways, is an effective tool in cancer treatment but is often difficult to execute due to varied solubility and pharmacokinetic differences between therapeutics. Use of a carrier system can alleviate many of the issues associated with combination therapy. Here we present a collagen peptide-based platform that allows for synchronous and colocalized cellular delivery of three different agents. The peptide is a hybrid of collagen and cell-penetrating peptide domains. The hybrid peptide assembles into a heterotrimer helix and forms a fully organic, high aspect ratio nanoparticle. The validity of the approach was tested with three chemically different agents Paclitaxel, Doxorubicin, and 5-Fluorouracil used in combination in clinical treatment of (ER)-positive and (PR)-positive breast cancer. The chemotherapy agents were first modified with a cleavable linker and then conjugated to the N-terminus of the peptides. After conjugation a series of variable temperature circular dichroism spectroscopy studies were performed to validate the formation of the heterotrimer. In addition, hybrid collagen/CPP peptides are known to enhance cellular uptake and improve solubility of drugs. The synergistic effect, in terms of enhanced efficacy, of the Paclitaxel-Doxorubicin-5-Fluorouracil combination was also calculated by cell viability studies. The design of this peptide-based drug delivery system provides several advantages: avoiding drug loading problems; removes the need for orthogonal synthesis and allows for colocalized delivery of up to three drugs.