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Co-delivery of TLR agonist with hypomethylating agent via an ultrasmall pro-drug micellar carrier for breast cancer chemoimmunotherapy

Zhang, Bei (2021) Co-delivery of TLR agonist with hypomethylating agent via an ultrasmall pro-drug micellar carrier for breast cancer chemoimmunotherapy. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Immunotherapies harness the host immune system to elicit durable and safer antitumor effects. But due to the cancer immune escape mechanisms, the therapeutic outcomes of immunotherapies are under expectations. Researchers have struggled for decades to develop strategies to make this attractive idea work better and to figure out the underlying mechanisms. In recent years, numerous reports indicated that the altered epigenetic modifications may play a critical role in tumor immune escape. The agents that can reprogram cells to a more normal status like demethylating agents were also demonstrated to potentiate immunotherapies. In this study, we designed and synthesized an ultrasmall pro-drug nanocarrier for co-delivery of a DNA demethylating agent azacitidine and an immune modulator R848. The small size nanoparticles could efficiently penetrate and deliver the combination therapies to tumor core and reduce the distribution in other major organs. These nanoparticles PAza-R848 effectively inhibited the tumor growth. In addition, they significantly increased the numbers of tumor-infiltrated CD45+ cells, and the percentages of CD4+ and CD8+ T cells and dendritic cells, which may contribute to the improved antitumor efficacy.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zhang, Beibez19@pitt.edubez190000-0002-4599-581X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLi, Songsol4@pitt.edusol4
Committee MemberSant, Shilpashs149@pitt.edushs1490000-0002-2017-9584
Committee MemberSun, Jingjingjis84@pitt.edujis84
Date: 20 April 2021
Date Type: Publication
Defense Date: 31 March 2021
Approval Date: 20 April 2021
Submission Date: 19 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 26
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: Nanoparticles, Breast Cancer, Combination therapies, Azacitidine, R848
Date Deposited: 20 Apr 2021 14:12
Last Modified: 20 Apr 2021 14:12
URI: http://d-scholarship.pitt.edu/id/eprint/40669

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