WAN, ZHUOYA
(2017)
TUNABLE IMMUNOSTIMULATORY NANOCARRIER FOR IMPROVING CANCER IMMUNOCHEMOTHERAPY.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Chemotherapy is the mainstream method of cancer therapy. In addition to direct cytotoxic effects on tumor cells, chemotherapy can induce antitumor immunity. The shortcomings of traditional chemotherapy are attributed to low solubility in aqueous solutions, rapid elimination, and lack of selectivity. In addition, cancers rapidly establish an immunological tolerance to the chemotherapy-induced antitumor immunity. The immune tolerance and suppression represent a major barrier to successful cancer treatment and are potential target for new therapeutics. Recent evidence demonstrates that an important mechanism underlying the immunological tolerance is the upregulated indoleamine-2,3-dioxygenase (IDO) expression in tumor cells or tumor-associated immune cells. Therefore, IDO pathway inhibition offers a potential for enhanced anti-tumor responses of chemotherapeutic agents.
In our previous study, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier, a PEG-modified prodrug of NLG919 (an IDO1 selective inhibitor), led to a significantly enhanced anti-tumor effect of PTX by reactivating immunogenic responses. In this study we examined the therapeutic potential of a new nanocarrier that is based on a prodrug of 1-methyl-d-trptophan (1-D-MT). 1-D-MT is also an IDO inhibitor but has been reported to enhance antitumor immunity via different mechanism. The nanocarrier will be developed via reversible addition fragmentation transfer (RAFT) polymerization. In addition to the simplicity of the synthesis of the nanocarrier, the amount of 1-D-MT that can be incorporated into the polymer can be readily tuned via controlling the degree of polymerization.
Two 1-D-MT-based monomers were first synthesized followed by RAFT polymerization to give well-defined di-block co-polymers. Several polymers were synthesized and they varied in the molar ratio of hydrophilic POEG block/hydrophobic 1-D-MT block and the type of linker. Preliminary data showed that a 1-D-MT polymer with ethylene glycol vinyl ether linker can only load limited amounts of PTX and doxorubicin (DOX). Introduction of a vinylbenzyl chloride linker led to an improvement in drug loading capacity. More studies on the biophysical and biological properties of the new carrier are currently underway.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
29 August 2017 |
| Date Type: |
Publication |
| Defense Date: |
3 August 2017 |
| Approval Date: |
29 August 2017 |
| Submission Date: |
21 August 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
47 |
| 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: |
Polymeric Micelles,Synergistic Effects,Immunochemotherapy, Breast Cancer Treatment |
| Date Deposited: |
29 Aug 2017 12:17 |
| Last Modified: |
29 Aug 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33072 |
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