Li, Shichen
(2024)
An HA-based targeting system for improved lung cancer treatment.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Platinum-based chemotherapy, such as cisplatin (CDDP), is a front-line treatment. However, the efficacy of platinum-related therapy is limited by the rapid development of drug resistance. Autophagy has been recognized as a critical factor in chemoresistance to CDDP. To overcome this, we introduced chloroquine (CQ) into the treatment, which is an effective autophagy inhibitor that can sensitize cancer cells to radiation and other anticancer drugs. To effectively co-deliver these two drugs, we developed a 5-aminosalicylic acid (5-ASA) derivatized nanocarrier based on hyaluronic acid (HA-ASA), which can actively target various types of cancer by targeting the overexpressed cell surface glycoprotein CD44.
We introduced 5-aminosalicylic acid (5-ASA) to the polymer (HA-ASA) as the hydrophobic core to form micelles. This novel nanocarrier can self-assemble in aqueous solution to form particles of ~100nm in size. Both CDDP and CQ can be loaded effectively into the HA-ASA micelles through various carrier/drug interactions with a final size of ~140 nm.
We showed that CDDP can induce autophagy in 3LL, FVBW17, and A549 cell lines and that the CDDP-CQ combination has a synergistic effect in vitro, with a combination index of smaller than 1. Meanwhile, we found that both CDDP and CQ can induce the expression of COX2, which can promote tumor progression, metastasis, and immunotherapy resistance. 5-ASA is an inhibitor of cyclooxygenase (COX), which can counteract the activity of the induced COX2.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
25 April 2024 |
| Date Type: |
Publication |
| Defense Date: |
28 March 2024 |
| Approval Date: |
25 April 2024 |
| Submission Date: |
23 April 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
22 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Non-small cell lung cancer; Nanoparticle; Drug delivery |
| Date Deposited: |
25 Apr 2024 16:07 |
| Last Modified: |
25 Apr 2024 16:07 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46252 |
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