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Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma

Nature Nanotechnology volume 18, pages 184–192 (2023)Cite this article

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An Author Correction to this article was published on 10 August 2023

An Author Correction to this article was published on 13 March 2023

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Abstract

Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma.

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Fig. 1: Synthesis and characterization of BPDs.
Fig. 2: Safety assessments of Btz-BPD.
Fig. 3: Btz-BPD provides substantial therapeutic enhancements over Btz in s.c. and aggressive orthotopic models of MM.
Fig. 4: Three-drug BPD CI studies.
Fig. 5: Improved therapeutic efficacy of synergistic three-drug BPD in MM mouse models (n = 5 mice per treatment group).

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All data supporting the findings of this study are available within the Article and its Supplementary Information and can also be obtained from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the NIH-NCI (1R01CA220468-01 (J.A.J., P.P.G.) and R01CA205954 (I.M.G.)), the Leukemia and Lymphoma Society and the National Science Foundation (Graduate Research Fellowship (H.V.-T.N.)) for supporting this research. This work was further supported in part by the Koch Institute Core Grant P30-CA14051 from the NCI. A.D. acknowledges support from the International Myeloma Foundation, the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFRMG) and Inserm Cancer. A.D., J.A.J. and I.M.G. acknowledge support from the Stand Up to Cancer Dream Team Multiple Myeloma grant. P.P.G. acknowledges the generous support of the Charles W. and Jennifer C. Johnson Clinical Investigator Fund as well as the Kathryn Fox Samway Foundation.

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Author notes

  1. These authors contributed equally: Alexandre Detappe, Hung V.-T. Nguyen.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Alexandre Detappe, Hung V.-T. Nguyen, Michael P. Agius, Clelia Mathieu, Nang K. Su, Irene M. Ghobrial & P. Peter Ghoroghchian

  2. Harvard Medical School, Boston, MA, USA

    Alexandre Detappe, Hung V.-T. Nguyen, Michael P. Agius, Clelia Mathieu, Nang K. Su, Irene M. Ghobrial & P. Peter Ghoroghchian

  3. Institut de Cancérologie Strasbourg Europe, Strasbourg, France

    Alexandre Detappe

  4. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Hung V.-T. Nguyen, Yivan Jiang, Wencong Wang, Samantha L. Kristufek & Jeremiah A. Johnson

  5. Window Therapeutics, Boston, MA, USA

    Hung V.-T. Nguyen & Yivan Jiang

  6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    David J. Lundberg & Sachin Bhagchandani

  7. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Jeremiah A. Johnson

  8. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Jeremiah A. Johnson

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Contributions

J.A.J., P.P.G., I.M.G., A.D. and H.V.-T.N. conceived the project idea. H.V.-T.N., Y.J., W.W. and S.L.K. synthesized and characterized the materials. A.D., M.P.A. and C.M. performed the biological experiments. D.J.L. performed the computational simulations. S.B. conducted the cryogenic electron microscopy studies. All authors helped in analysing the results. J.A.J., P.P.G., I.M.G., A.D. and H.V.-T.N. wrote the paper. All authors read and edited the manuscript.

Corresponding authors

Correspondence to Irene M. Ghobrial, P. Peter Ghoroghchian or Jeremiah A. Johnson.

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Competing interests

A.D., H.V.-T.N., Y.J., I.M.G., P.P.G. and J.A.J. are named inventors on a patent application (US patent application no. 16/825,269) jointly filed by the Massachusetts Institute of Technology and the Dana-Farber Cancer Institute on the Btz macromolecular PIs described in this work. H.V.-T.N., Y.J. and J.A.J. are co-founders and shareholders of Window Therapeutics, which seeks to translate this technology to clinical cancer therapies. The other authors declare no competing interests.

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Nature Nanotechnology thanks Jo Caers, Twan Lammers and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–37, Tables 1 and 2, materials/general methods/instrumentation and synthesis procedures.

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Detappe, A., Nguyen, H.VT., Jiang, Y. et al. Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma. Nat. Nanotechnol. 18, 184–192 (2023). https://doi.org/10.1038/s41565-022-01310-1

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