| Reference | 1. Int J Immunopathol Pharmacol. 2017 Sep;30(3):215-226. doi:
10.1177/0394632017714696. Epub 2017 Jun 12.
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Combinatorial antitumor effects of indoleamine 2,3-dioxygenase inhibitor NLG919
and paclitaxel in a murine B16-F10 melanoma model.
<br><br>
Meng X(1), Du G(1), Ye L(2), Sun S(1), Liu Q(1), Wang H(1), Wang W(1), Wu Z(1),
Tian J(1).
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Author information: <br>
(1)1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug
Evaluation (Yantai University), Ministry of Education, Collaborative Innovation
Center of Advanced Drug Delivery System and Biotech Drugs in Universities of
Shandong, Yantai University, Yantai, P.R. China.
(2)2 School of Public Health and Management, Institute of Toxicology, Binzhou
Medical University, Yantai, P.R. China.
<br>
Indoleamine 2,3-dioxygenase (IDO) is involved in tumor immune escape and
resistance to chemotherapy, and is clinically correlated with tumor progression.
IDO inhibitors show marginal efficacy as single agents; therefore, combinations
of these inhibitors with other therapies hold promise for cancer therapy. The aim
of this study was to investigate the synergistic antitumor effects of IDO
inhibitor NLG919 in combination with different regimens of paclitaxel in a murine
B16-F10 melanoma model. NLG919 increased the cytotoxic activity of paclitaxel
toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in
vitro. In B16-F10 tumor-bearing mice, NLG919 was uniformly distributed throughout
tumors and decreased kynurenine levels and kynurenine/tryptophan ratios in tumors
and plasma for 6-12 h. NLG919 suppressed tumor growth in a dose-dependent manner
and exhibited maximum efficacy at 100 mg/kg. In combination with different
regimens of paclitaxel, NLG919 displayed synergistic antitumor effects, and
NLG919 did not increase the side effects of paclitaxel. Within the tumors, the
percentage of CD3+, CD8+, and CD4+ T cells and secretion of IFN-γ and
interleukin-2 were synergistically increased, whereas the percentage of CD4+CD25+
regulatory T cells was decreased. NLG919 can potentiate the antitumor efficacy of
paclitaxel without increasing its side effects, suggesting that the combination
of IDO inhibitor-based immunotherapy with chemotherapy could be a potential
strategy for cancer treatment.
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2. Acta Pharmacol Sin. 2017 Jun;38(6):823-834. doi: 10.1038/aps.2017.44. Epub 2017
May 8.
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Programmable co-delivery of the immune checkpoint inhibitor NLG919 and
chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric
prodrug carrier.
<br><br>
Sun JJ(1)(2)(3), Chen YC(1)(2)(3), Huang YX(1)(2)(3), Zhao WC(2), Liu YH(4),
Venkataramanan R(2), Lu BF(3)(5), Li S(1)(2)(3).
<br>
Author information: <br>
(1)Center for Pharmacogenetics.
(2)Department of Pharmaceutical Sciences, School of Pharmacy.
(3)University of Pittsburgh Cancer Institute, University of Pittsburgh,
Pittsburgh, PA 15261, USA.
(4)Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University,
Yinchuan 750004, China.
(5)Department of Immunology, School of Medicine, University of Pittsburgh,
Pittsburgh, PA 15261, USA.
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To achieve synergistic therapeutic efficacy and prevent cancer relapse,
chemotherapy and immunotherapy have been combined as a new modality for tumor
treatment. In this work, we designed a redox-responsive immunostimulatory
polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune
checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX).
NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized
micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10
micelles displayed spherical morphology with a size of ～170 nm. DOX was
effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In
vitro DOX release studies showed that rapid drug release could be achieved in the
highly redox environment after intracellular uptake by tumor cells. In 4T1.2
tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and
NLG in the tumor tissues compared with other organs. The PSSN10 carrier
dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02
co-culture experiments, and significantly inhibited tumor growth in vivo.
DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse
breast cancer cells and PC-3 human prostate cancer cells comparable to that of
DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was
more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX
in inhibiting the tumor growth and prolonging the survival of the treated mice.
In addition, a more immunoactive tumor microenvironment was observed in the mice
treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment
groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in
synergistic anti-tumor activity.
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