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]W5 were 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.
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.
","abstract_html":"<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 [R<sub>5</sub>K]W<sub>5</sub>, [R<sub>6</sub>K]W<sub>5</sub>, [R<sub>5</sub>K]W<sub>6</sub>, [R<sub>7</sub>K]W<sub>5</sub>, [R<sub>5</sub>K]W<sub>7</sub>, [R<sub>6</sub>K]W<sub>6</sub>, and [R<sub>7</sub>K]W<sub>7</sub> 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). [R<sub>6</sub>K]W<sub>6</sub> and [R<sub>5</sub>K]W<sub>5 </sub>were 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 [R<sub>5</sub>K]W<sub>7</sub>A and linear peptide R<sub>5</sub>KW<sub>7</sub>A, 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 [R<sub>5</sub>K]W<sub>7</sub>A-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, [R<sub>5</sub>K]W<sub>7</sub>A-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>","abstract_has_math":false,"creators":["Mozaffari, Saghar"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Pharmaceutical Sciences","degree_department":null,"school":null,"contributors":["Dr. Keykavous Parang","Dr. Rakesh Tiwari","Dr. Innokenity Maslennikov","Dr. Jason Yamaki"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-12-18T08:00:00Z","date_published":"2019-12-18T08:00:00Z","updated_at":"2026-07-24T01:38:09Z","subjects":["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"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dr. Keykavous Parang","Dr. Rakesh Tiwari","Dr. Innokenity Maslennikov","Dr. Jason Yamaki"]},{"key":"dc:creator","label":"Author","values":["Mozaffari, Saghar"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2022-01-14T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmaceutical Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["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"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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]W5 were 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.
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.
"]},{"key":"dc:source","label":"Dc Source","values":["Mozaffari S. Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System. [dissertation]. Irvine, CA: Chapman University; 2019. https://doi.org/10.36837/chapman.000107"]},{"key":"dc:title","label":"Title","values":["Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System"]}]}],"canonical_facts":{"dc:contributor":["Dr. Keykavous Parang","Dr. Rakesh Tiwari","Dr. Innokenity Maslennikov","Dr. Jason Yamaki"],"dc:creator":["Mozaffari, Saghar"],"dc:date.available":["2022-01-14T08:00:00Z"],"dc:description.abstract":["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]W5 were 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.
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.
"],"dc:identifier":["https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2"],"dc:source":["Mozaffari S. Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System. [dissertation]. Irvine, CA: Chapman University; 2019. https://doi.org/10.36837/chapman.000107"],"dc:subject":["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"],"dc:title":["Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System"],"thesis:degree_discipline":["Pharmaceutical Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T01:38:09Z"}