2. Academic Validation
  3. Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer

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

  • Nat Nanotechnol. 2021 Jul;16(7):830-839. doi: 10.1038/s41565-021-00897-1.
Ran Li 1 2,  Thomas S C Ng 1 2,  Stephanie J Wang 1 3,  Mark Prytyskach 1,  Christopher B Rodell 1 4,  Hannes Mikula 1 5,  Rainer H Kohler 1,  Michelle A Garlin 1,  Douglas A Lauffenburger 3,  Sareh Parangi 6,  Daniela M Dinulescu 7,  Nabeel Bardeesy 8,  Ralph Weissleder 9 10 11,  Miles A Miller 12 13
Affiliations

Affiliations

  • 1 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • 2 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 3 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4 School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
  • 5 Institute of Applied Synthetic Chemistry, Vienna University of Technology (TU Wien), Vienna, Austria.
  • 6 Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • 7 Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 8 MGH Cancer Center, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • 9 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA. [email protected].
  • 10 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • 11 Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected].
  • 12 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA. [email protected].
  • 13 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 33958764 DOI: 10.1038/s41565-021-00897-1
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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