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Dual Functional Immunostimulatory Polymeric Prodrug Carrier with Pendent Indoximod for Enhanced Cancer Immunochemotherapy

44 Pages Posted: 24 Jan 2019 First Look: Preprint

See all articles by Zhuoya Wan

Zhuoya Wan

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Jingjing Sun

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Jieni Xu

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Pearl Moharil

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Jing Chen

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Junchi Xu

University of Pittsburgh - Department of Immunology; The Fifth People’s Hospital of Suzhou - Testing Center

Jiang Li

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Pengfei Xu

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Xiaochao Ma

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Wen Xie

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Bingfeng Lu

University of Pittsburgh - Department of Immunology

Song Li

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences

Abstract

Immunotherapy based on checkpoint blockade has been regarded as one of the most promising approaches towards many types of cancers. However, low response rate hinders their application due to insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. To achieve an overall enhanced therapeutic outcome, we developed a dual-functional immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor, which can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulted carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed that ICD-triggered Dox promoted intra-tumoral infiltration of CD8+ T cells and IFN-γ-production by CD8+ T cells. Meanwhile, cleaved indoximod significantly increased CD8+ T cell infiltration while reducing the immunosuppressive T regulatory cells (Tregs). More importantly, Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded inert micelle carrier (POEG-b-PVB micelle) and POEG-b-PVBIND micelles alone, confirming synergistic effect of indoximod and Dox in improving the overall antitumor activity.

Keywords: Indoximod, Immunochemotherapy, Indoleamine 2,3-dioxygenase, Immuno-oncology

Suggested Citation

Wan, Zhuoya and Sun, Jingjing and Xu, Jieni and Moharil, Pearl and Chen, Jing and Xu, Junchi and Li, Jiang and Xu, Pengfei and Ma, Xiaochao and Xie, Wen and Lu, Bingfeng and Li, Song, Dual Functional Immunostimulatory Polymeric Prodrug Carrier with Pendent Indoximod for Enhanced Cancer Immunochemotherapy (January 23, 2019). Available at SSRN: https://ssrn.com/abstract=3320735

Zhuoya Wan (Contact Author)

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Jingjing Sun

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Jieni Xu

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Pearl Moharil

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Jing Chen

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Junchi Xu

University of Pittsburgh - Department of Immunology

Pittsburgh, PA 15261
United States

The Fifth People’s Hospital of Suzhou - Testing Center

Suzhou, 215007
China

Jiang Li

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Pengfei Xu

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Xiaochao Ma

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Wen Xie

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

Bingfeng Lu

University of Pittsburgh - Department of Immunology

Pittsburgh, PA 15261
United States

Song Li

University of Pittsburgh - Center for Pharmacogenetics ( email )

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences ( email )

Pittsburgh, PA 15261
United States

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