Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System

<p>A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R₅K]W₅, [R₆K]W₅, [R₅K]W₆, [R₇K]W₅, [R₅K]W₇, [R₆K]W₆, and [R₇K]W₇ were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively charged arginine residues on the ring and hydrophobic tryptophan residues in a sequential linear outside the ring was an optimal approach to improve the intracellular uptake of cargo molecules through non-covalent interactions. Some of these peptides were also evaluated for their efficiency for intracellular delivery of siRNA to triple-negative breast cancer cell lines in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). [R₆K]W₆ and [R₅K]W₅were found to be very efficient in the delivery of siRNA. Furthermore, co-formulation of peptides with lipid DOPE significantly enhanced the efficiency of siRNA delivery compared to peptide alone. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides.</p> <p>A chemotherapeutic drug, doxorubicin (Dox) was covalently conjugated to the cyclic peptide [R₅K]W₇A and linear peptide R₅KW₇A, and the biological activity was evaluated in cell-based assays. Comparative antiproliferative assays between covalently conjugated peptide-Dox and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. The conjugation of Dox with cyclic [R₅K]W₇A-Dox exhibited similar antiproliferative activity compared to Dox alone after 72 h incubation time in all cancer cell lines, such as leukemia, ovarian and gastric cancer cells. However, [R₅K]W₇A-Dox significantly reduced the cell cytotoxicity in normal cell lines such as normal heart muscle and normal kidney cells after 72 h when compared with Dox alone. These results revealed that this cyclic peptide prodrug can be used as a potential candidate for the treatment of cancer cells with reduced side effects against normal cells in the body. <strong></strong></p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2019

Author dc:creator

• Mozaffari, Saghar

Contributors dc:contributor

• Dr. Keykavous Parang
• Dr. Rakesh Tiwari
• Dr. Innokenity Maslennikov
• Dr. Jason Yamaki

• Cell-Penetrating
• Peptide
• Drug Delivery
• siRNA
• Cancer
• cell
• Amino Acids, Peptides, and Proteins
• Chemical Actions and Uses
• Medicinal and Pharmaceutical Chemistry
• Pharmaceutics and Drug Design

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_dissertations-1001