An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy.
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 PEG2k-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 PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Yichao
Y
Chen
Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Rui
R
Xia
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Yixian
Y
Huang
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Wenchen
W
Zhao
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Jiang
J
Li
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Xiaolan
X
Zhang
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Pengcheng
P
Wang
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Raman
R
Venkataramanan
Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Jie
J
Fan
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Wen
W
Xie
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Xiaochao
X
Ma
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Binfeng
B
Lu
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Song
S
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D054833:Isoindoles / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D017239:Paclitaxel; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
C000626065:1-cyclohexyl-2-(5H-imidazo(5,1-a)isoindol-5-yl)ethanol; D000970:Antineoplastic Agents; D004337:Drug Carriers; D007093:Imidazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D054833:Isoindoles; D008823:Micelles; D058726:Nanoconjugates; D011355:Prodrugs; D011092:Polyethylene Glycols; D017239:Paclitaxel