An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy

Yichao Chen; Rui Xia; Yixian Huang; Wenchen Zhao; Jiang Li; Xiaolan Zhang; Pengcheng Wang; Raman Venkataramanan; Jie Fan; Wen Xie; Xiaochao Ma; Binfeng Lu; Song Li

doi:10.1038/ncomms13443

An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy

Nat Commun. 2016 Nov 7:7:13443. doi: 10.1038/ncomms13443.

Authors

Yichao Chen^{1

2

3}, Rui Xia⁴, Yixian Huang^{1

2

3}, Wenchen Zhao², Jiang Li^{1

2

3}, Xiaolan Zhang^{1

2

3}, Pengcheng Wang^{1

2}, Raman Venkataramanan², Jie Fan⁵, Wen Xie^{1

2}, Xiaochao Ma^{1

2}, Binfeng Lu^{3

4}, Song Li^{1

2

3}

Affiliations

¹ Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
² Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
³ University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
⁴ Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
⁵ Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

Abstract

Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG_2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG_2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / immunology*
Antineoplastic Agents / pharmacology
Breast Neoplasms / immunology
Breast Neoplasms / therapy*
Cell Line, Tumor
Drug Carriers / chemistry
Drug Carriers / pharmacology
Female
Humans
Imidazoles / chemistry
Imidazoles / immunology*
Imidazoles / pharmacology
Immunotherapy / methods*
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
Isoindoles / chemistry
Isoindoles / immunology*
Isoindoles / pharmacology
Mice
Mice, Inbred BALB C
Mice, Nude
Micelles
Nanoconjugates / administration & dosage
Nanoconjugates / chemistry
Paclitaxel
Polyethylene Glycols / administration & dosage
Polyethylene Glycols / chemistry
Prodrugs / chemistry
Prodrugs / pharmacology
Tissue Distribution
Treatment Outcome
Xenograft Model Antitumor Assays

Substances

1-cyclohexyl-2-(5H-imidazo(5,1-a)isoindol-5-yl)ethanol
Antineoplastic Agents
Drug Carriers
Imidazoles
Indoleamine-Pyrrole 2,3,-Dioxygenase
Isoindoles
Micelles
Nanoconjugates
Prodrugs
Polyethylene Glycols
Paclitaxel

Abstract

Publication types

MeSH terms

Substances

Grants and funding