TY - JOUR
T1 - Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy
AU - Wang, Zhiren
AU - Little, Nicholas
AU - Chen, Jiawei
AU - Lambesis, Kevin Tyler
AU - Le, Kimberly Thi
AU - Han, Weiguo
AU - Scott, Aaron James
AU - Lu, Jianqin
N1 - Funding Information:
This work was supported in part by a Startup Fund from the College of Pharmacy at the University of Arizona and two Seed Grants from the University of Arizona BIO5 Institute and the State of Arizona’s Technology and Research Initiative Fund (TRIF), and by National Institutes of Health (NIH) grants (NIEHS P30 ES006694, NCI P30 CA023074 and NCI R01 CA092596). We acknowledge Statistical Consulting at the University of Arizona Information Technology for their assistance with the statistical analysis; the use of mass spectrometry equipment in the Analytical and Biological Mass Spectrometry Core Facility at the University of Arizona BIO5 Institute; the University of Arizona Translational Bioimaging Resource Core for the Lago live animal imaging; the University of Arizona University Animal Care Pathology Services for the serum chemistry and haematological counts; the TACMASR of the UACC for the IHC and H&E staining, immunofluorescence and confocal laser scanning microscopy; and Arizona State University’s John Cowley Center for High Resolution Electron Microscopy (the specific instrumentation used was supported by the National Science Foundation (NSF), MRI grant NSF1531991) for the cryo-EM.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/10
Y1 - 2021/10
N2 - Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch ‘immune-cold’ tumours to ‘immune-hot’ to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.
AB - Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch ‘immune-cold’ tumours to ‘immune-hot’ to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.
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U2 - 10.1038/s41565-021-00950-z
DO - 10.1038/s41565-021-00950-z
M3 - Article
C2 - 34385682
AN - SCOPUS:85112687564
VL - 16
SP - 1130
EP - 1140
JO - Nature Nanotechnology
JF - Nature Nanotechnology
SN - 1748-3387
IS - 10
ER -