Development of a Lung Cancer Targeting Peptide for Imaging and Drug Delivery
| dc.contributor.advisor | Corbin, Ian R. | en |
| dc.contributor.committeeMember | Brown, Kathlynn C. | en |
| dc.contributor.committeeMember | Kohler, Jennifer J. | en |
| dc.contributor.committeeMember | Minna, John D. | en |
| dc.creator | Allred, Curtis Arlin | en |
| dc.date.accessioned | 2020-09-01T21:02:58Z | |
| dc.date.available | 2020-09-01T21:02:58Z | |
| dc.date.created | 2018-08 | |
| dc.date.issued | 2018-04-12 | |
| dc.date.submitted | August 2018 | |
| dc.date.updated | 2020-09-01T21:02:59Z | |
| dc.description | Pages 25-120 are misnumbered as pages 27-122. | en |
| dc.description.abstract | Lung cancer kills more people in the United Stated than the next three biggest cancer killers combined. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer patients and has an overall estimated 5-year survival of 18% in 2017. The emergence of targeted therapies (molecularly guided treatment) has improved the overall survival and quality of life of ~20% of NSCLC patients. A different molecularly guided treatment modality, targeting therapy, has shown success in other cancer types, but has not yet been successfully applied in NSCLC. Peptides are a class of molecules that have demonstrated exquisite targeting of cancer cells. HCC15.2 peptide was identified from a phage display library screen on NSCLC cells. It binds to an unknown receptor on a specific subset of NSCLC patient samples (24%) and cell lines (50%), which is not present in immortalized but non-transformed human bronchial epithelial cells (HBEC). Not only does HCC15.2 have a high affinity of ~5 nM and high specificity, it also triggers internalization and delivers its cargo into the cancer cell. HCC15.2 was optimized by altering the multimerization and amino acid content and protecting it from serum degradation. After the optimizations, HCC15.2 was shown to deliver many cargo types into cancer cells which traffic to and accumulate in lysosomes. HCC15.2 also demonstrated its ability to home to a subcutaneous xenograft in mice ~30-fold better than non-targeted dye after systemic delivery. This peptide used in molecular imaging could aid in earlier tumor detection, which correlates with better patient survival. HCC15.2 conjugated to saporin, a ribosome inactivating protein, showed an IC50 of 5.4 nM in in vitro viability assays. Delivery of saporin by HCC15.2 significantly slowed the growth of tumor xenografts. HCC15.2 is a perfect candidate for molecularly guided imaging and therapy. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1192325698 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/8781 | |
| dc.language.iso | en | en |
| dc.subject | Antineoplastic Agents | en |
| dc.subject | Carcinoma, Non-Small-Cell Lung | en |
| dc.subject | Molecular Imaging | en |
| dc.subject | Molecular Targeted Therapy | en |
| dc.subject | Peptides | en |
| dc.subject | Small Cell Lung Carcinoma | en |
| dc.title | Development of a Lung Cancer Targeting Peptide for Imaging and Drug Delivery | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Cancer Biology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |