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Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy

Abstract

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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Fig. 1: Development of SM-derived CPT liposomal nanovesicles (camptothesomes).
Fig. 2: Camptothesomes increased the MTD of CPT without inducing systemic toxicities in healthy mice.
Fig. 3: Improved circulation half-life and tumour delivery with efficient intratumoral drug release and deep tumour penetration.
Fig. 4: Camptothesome synergizes with PD-L1/PD-1 blockade to eradicate CRC tumours.
Fig. 5: Co-encapsulating DOX-IND in camptothesome-4 using DOX as a transmembrane-enabling carrier.
Fig. 6: Eradication of advanced and metastatic orthotopic CRC and subcutaneous melanoma tumours.

Data availability

The data supporting the findings of this study are available within the article and the Supplementary Information. All relevant data are available from the authors upon reasonable request.

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Acknowledgements

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.

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J.L. conceived and supervised the project. J.L. and Z.W. designed the experiments, analysed the data and wrote the manuscript. Z.W. performed the experiments. N.L., J.C., K.T.L. and K.T.L. assisted in the prodrug synthesis, nanoparticle preparation, HPLC and in vivo animal studies. W.H. assisted with the PCR assay. A.J.S. provided clinical research insight into antitumour efficacy studies. All of the authors discussed the results and commented on the manuscript.

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Correspondence to Jianqin Lu.

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J.L. has applied for patents related to this study. The other authors have no competing interests.

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Wang, Z., Little, N., Chen, J. et al. Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy. Nat. Nanotechnol. 16, 1130–1140 (2021). https://doi.org/10.1038/s41565-021-00950-z

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