Immunochemotherapy that combines a chemotherapeutic agent with an immune checkpoint blocker represents one of the most promising strategies for the treatment of various types of cancers including breast cancer. However, its success is limited by a number of issues including: a) the poor water solubility of the drug(s); and b) the challenge in simultaneous delivery of the two therapeutics to the tumors. We have developed a dual-functional, immunostimulatory nanomicellar carrier that was based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumor immune suppression. We showed that PEG-NLG alone was effective in enhancing T cell immune responses and exhibited significant antitumor activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG-NLG nanocarrier led to a significantly improved antitumor response in murine models of breast cancer. This application is focused on further improving this delivery system to facilitate drug release at tumor site. The potential of the improved nanocarrier in synergistic delivery of anticancer agents will then be investigated.
Three specific aims will be pursued in this proposal.
Aim 1 will develop an improved PEG-NLG-based delivery system with facilitated drug release following delivery to tumors.
Aim 2 will examine the biodistribution and pharmacokinetics of the improved delivery system in murine breast cancer models. We will first define the stability of the improved delivery system in blood circulation. The efficiency of the system in delivery of PTX is then examined.
Aim 3 will define the in vivo therapeutic effect of PTX formulated in the improved delivery system in murine models of breast cancer. The underlying mechanism for the synergistic antitumor activity will also be studied. Successful completion of this study will lead to the development of a novel strategy for improved breast cancer immunochemotherapy.

Public Health Relevance

This study is to develop an immunostimulatory nanocarrier for synergistic delivery of chemotherapeutic drugs. Successful completion of this study may lead to the development of a novel immunochemotherapy to improve the treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA219399-03
Application #
9702767
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2017-06-13
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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Li, Zuojun; Sun, Jingjing; Huang, Yixian et al. (2018) A Nanomicellar Prodrug Carrier Based on Ibuprofen-Conjugated Polymer for Co-delivery of Doxorubicin. Front Pharmacol 9:781
Xu, Jieni; Sun, Jingjing; Wang, Pengcheng et al. (2018) Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs. J Drug Target 26:448-457