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Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer

Nature Nanotechnology volume 16, pages 830–839 (2021)Cite this article

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Abstract

Nanoparticulate albumin bound paclitaxel (nab-paclitaxel, nab-PTX) is among the most widely prescribed nanomedicines in clinical use, yet it remains unclear how nanoformulation affects nab-PTX behaviour in the tumour microenvironment. Here, we quantified the biodistribution of the albumin carrier and its chemotherapeutic payload in optically cleared tumours of genetically engineered mouse models, and compared the behaviour of nab-PTX with other clinically relevant nanoparticles. We found that nab-PTX uptake is profoundly and distinctly affected by cancer-cell autonomous RAS signalling, and RAS/RAF/MEK/ERK inhibition blocked its selective delivery and efficacy. In contrast, a targeted screen revealed that IGF1R kinase inhibitors enhance uptake and efficacy of nab-PTX by mimicking glucose deprivation and promoting macropinocytosis via AMPK, a nutrient sensor in cells. This study thus shows how nanoparticulate albumin bound drug efficacy can be therapeutically improved by reprogramming nutrient signalling and enhancing macropinocytosis in cancer cells.

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Fig. 1: Nab-PTX accumulates in cancer cells distinctly from other nanoformulations.
Fig. 2: RAS signalling drives nab-PTX uptake by cancer cells.
Fig. 3: Cancer-cell RAS signalling drives in vivo tumour accumulation of nab-PTX.
Fig. 4: MEK1/2 inhibition via trametinib reduces nab-PTX uptake and efficacy.
Fig. 5: IGF1R inhibitor enhances uptake of nab-PTX in an AMPK- and macropinocytosis-dependent manner.
Fig. 6: IGF1R-targeted kinase inhibitor enhances nab-PTX uptake and efficacy in vivo.

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Data availability

All data are available from corresponding authors upon request. RNA-seq data used to calculate the MAPK/AMPK activity score for each cell line were obtained from the Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle).

Code availability

This study did not generate new custom code or mathematical algorithms.

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Acknowledgements

We acknowledge S. Schmidt and G. Wojtkiewicz for assistance with imaging and biodistribution through the MGH-CSB MIP program. Part of this work was supported by NIH/NCI grant nos. R00CA207744 (M.A.M), DP2CA259675 (M.A.M), U01CA206997 (R.W.), R01HL131495 (R.W.), R01CA206890 (R.W.), T32CA079443 (R.L.), R01GM069668 (D.A.L.), R01CA96504 (D.A.L.), U54CA112967 (D.A.L.), U54CA217377 (D.A.L.), the NSF Graduate Research Fellowship Program (S.J.W.), the American Cancer Society-Ellison Foundation Postdoctoral Fellowship PF-20-106-01-LIB (R.L.), MGH FMD Fellowship (R.L.) and an American Thyroid Association/Thyroid Cancer Survivors’ Association Research Grant (T.S.C.N.).

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Authors and Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA

    Ran Li, Thomas S. C. Ng, Stephanie J. Wang, Mark Prytyskach, Christopher B. Rodell, Hannes Mikula, Rainer H. Kohler, Michelle A. Garlin, Ralph Weissleder & Miles A. Miller

  2. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Ran Li, Thomas S. C. Ng, Ralph Weissleder & Miles A. Miller

  3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Stephanie J. Wang & Douglas A. Lauffenburger

  4. School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA

    Christopher B. Rodell

  5. Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria

    Hannes Mikula

  6. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Sareh Parangi

  7. Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Daniela M. Dinulescu

  8. MGH Cancer Center, Massachusetts General Hospital Research Institute, Boston, MA, USA

    Nabeel Bardeesy

  9. Department of Systems Biology, Harvard Medical School, Boston, MA, USA

    Ralph Weissleder

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  1. Ran Li
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Contributions

R.L., R.W. and M.A.M. developed the concept. R.L., T.S.C.N., S.J.W., C.B.R., H.M., N.B., R.W. and M.A.M designed the experiments. R.L., T.S.C.N., S.J.W, M.P., C.B.R, H.M., R.H.K. and M.A.G. performed the experiments. R.L., R.W. and M.A.M. wrote the paper. R.L., T.S.C.N., S.J.W., M.P., C.B.R., H.M., R.H.K., M.A.G., D.A.L., S.P., D.M.D., N.B., R.W. and M.A.M. analysed the results and edited the paper.

Corresponding authors

Correspondence to Ralph Weissleder or Miles A. Miller.

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Competing interests

R.W. is a cofounder of T2Biosystems and Lumicell, serves as a scientific adviser for ModeRNA Therapeutics, Tarveda Therapeutics and Alivio Therapeutics. None of these activities are related to the paper. The other authors declare that they have no competing interests.

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

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Li, R., Ng, T.S.C., Wang, S.J. et al. Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer. Nat. Nanotechnol. 16, 830–839 (2021). https://doi.org/10.1038/s41565-021-00897-1

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