TY - JOUR
T1 - Liposomal delivery of mitoxantrone and a cholesteryl indoximod prodrug provides effective chemo-immunotherapy in multiple solid tumors
AU - Mei, Kuo Ching
AU - Liao, Yu Pei
AU - Jiang, Jinhong
AU - Chiang, Michelle
AU - Khazaieli, Mercedeh
AU - Liu, Xiangsheng
AU - Wang, Xiang
AU - Liu, Qi
AU - Hyun Chang, Chong
AU - Zhang, Xiao
AU - Li, Juan
AU - Ji, Ying
AU - Melano, Brenda
AU - Telesca, Donatello
AU - Xia, Tian
AU - Nel, Andre E.
AU - Meng, Huan
N1 - Funding Information:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Nos. U01CA198846 and 1R01CA247666-01A1. NAMMI Therapeutics provided a SRA. We thank the Translational Pathology Core Laboratory (TPCL) at UCLA Jonsson Comprehensive Cancer Center for IHC staining, the Electron Imaging Center for Nanomachines the use of EM instruments, the Molecular Instrumentation Center for NMRs and Mass Spectrometry, and the CNSI Advanced Light Microscopy/Spectroscopy Shared Facility for confocal fluorescent microscopy.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/10/27
Y1 - 2020/10/27
N2 - We developed a custom-designed liposome carrier for codelivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3- dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterolconjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK) cell, which suggests a different type of ICD response. The immunotherapy response was significantly augmented by codelivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg, and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND codelivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by codelivery of an IDO-1 pathway inhibitor.
AB - We developed a custom-designed liposome carrier for codelivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3- dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterolconjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK) cell, which suggests a different type of ICD response. The immunotherapy response was significantly augmented by codelivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg, and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND codelivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by codelivery of an IDO-1 pathway inhibitor.
KW - "2-in-1" codelivery liposome
KW - And cholesterol prodrug
KW - Chemo-immunotherapy
KW - IDO-1
KW - Immunogenic cell death
KW - Mitoxantrone
UR - http://www.scopus.com/inward/record.url?scp=85094982900&partnerID=8YFLogxK
U2 - 10.1021/acsnano.0c05194
DO - 10.1021/acsnano.0c05194
M3 - Journal article
C2 - 32940463
AN - SCOPUS:85094982900
SN - 1936-0851
VL - 14
SP - 13343
EP - 13366
JO - ACS Nano
JF - ACS Nano
IS - 10
ER -