Chen, Yuang
(2023)
Engineering Nanoparticles for Cancer Therapy.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
There has been significant progress in the field of nanoparticles (NPs) recently, leading to their widespread use in various clinical applications, especially in cancer therapy. NPs have been specifically designed to address the limitations of conventional therapeutics and successfully navigate through diverse biological barriers that vary among patients and diseases. Current development focuses on the engineering of NPs with increasing precision to tailor drug and gene delivery in a more accurate manner, ushering in the era of precision medicine against cancer.
In this thesis, I explored the sophisticated designs of two different NPs used in both local and systemic applications for cancer therapy. In the first study, I focused on vaccine delivery assisted by NPs for cancer immunotherapy. NP-mediated vaccination can efficiently deliver neoantigenic nucleic acids into lymphoid organs and antigen presenting cells. The intracellular release of vaccine and cross-presentation of antigens can be fine-tuned via polymer engineering. Polyethylenimine (PEI) was conjugated with farnesylthiosalicylic acid (FTS), an inhibitor of RAS signaling, and the resulting amphiphilic conjugate could self-assemble to form micelles. In vivo delivery of endogenous melanoma neoantigen tyrosinase-related protein 2 (Trp2) gained substantial local tumor inhibition and systemic protection. FTS-PEI represents a promising transfection agent for effective gene delivery to tumors and draining lymph nodes to mediate neoantigen vaccination.
In the second study, a novel NP was developed that is effective in codelivering of siRNA and chemotherapeutic drugs. This NP is highly effective in tumor targeting through both EPR and targeting of tumor vasculature. Codelivery of Xkr8 siRNA and FuOXP (a prodrug conjugate of 5-FU and oxoplatin) led to significant improvements in antitumor activity in colon and pancreatic cancer models along with increase in CD45+ cells, decrease in Treg cells, and reversal of FuOXP-induced decrease in M1/M2-like ratio. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
11 September 2023 |
| Date Type: |
Publication |
| Defense Date: |
17 August 2023 |
| Approval Date: |
11 September 2023 |
| Submission Date: |
31 August 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
107 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Nanoparticle Cancer therapy |
| Date Deposited: |
11 Sep 2023 17:40 |
| Last Modified: |
11 Sep 2023 17:40 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45369 |
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