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Journal article
Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer
Nature nanotechnology, v 16(7), pp 830-839
01 Jul 2021
PMID: 33958764
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Nanoparticle albumin bound paclitaxel (nab-PTX) is widely used in the clinic to treat different cancers, but the effect of albumin on the distribution of the drug in tumours is not clear. Here the authors show that the accumulation of nab-PTX in tumours is affected by signalling molecules involved in nutrient uptake and processing, which could be reprogrammed to increase the drug's efficacy.
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Details
- Title
- Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer
- Creators
- Thomas S. C. Ng - Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USAStephanie J. Wang - Center for Systems BiologyMark Prytyskach - Center for Systems BiologyChristopher B. Rodell - Drexel UniversityHannes Mikula - Center for Systems BiologyRainer H. Kohler - Center for Systems BiologyMichelle A. Garlin - Center for Systems BiologyDouglas A. Lauffenburger - Massachusetts Institute of TechnologySareh Parangi - Massachusetts General HospitalDaniela M. Dinulescu - Brigham and Women's HospitalNabeel Bardeesy - Massachusetts General HospitalRalph Weissleder - Harvard UniversityMiles A. Miller - Massachusetts General Hospital
- Publication Details
- Nature nanotechnology, v 16(7), pp 830-839
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 14
- Grant note
- American Thyroid Association/Thyroid Cancer Survivors' Association Research Grant PF-20-106-01-LIB / American Cancer Society-Ellison Foundation Postdoctoral Fellowship MGH FMD Fellowship R00CA207744; DP2CA259675; U01CA206997; R01HL131495; R01CA206890; T32CA079443; R01GM069668; R01CA96504; U54CA112967; U54CA217377 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) NSF Graduate Research Fellowship Program; National Science Foundation (NSF)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000648069500003
- Scopus ID
- 2-s2.0-85105405847
- Other Identifier
- 991019167866604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Materials Science, Multidisciplinary
- Nanoscience & Nanotechnology