Open AccessTherapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer
Author(s) -
Ran Li,
Thomas S.C. Ng,
Stephanie J. Wang,
Mark Prytyskach,
Christopher B. Rodell,
Hannes Mikula,
Rainer H. Köhler,
Michelle A. Garlin,
Douglas A. Lauffenburger,
Sareh Parangi,
Daniela M. Dinulescu,
Nabeel Bardeesy,
Ralph Weissleder,
Miles A. Miller
Publication year - 2021
Publication title -
nature nanotechnology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 14.308
H-Index - 353
eISSN - 1748-3395
pISSN - 1748-3387
DOI - 10.1038/s41565-021-00897-1
Subject(s) - paclitaxel , cancer research , albumin , cancer cell , pharmacology , drug delivery , pinocytosis , cancer , chemistry , biology , medicine , cell , biochemistry , endocytosis , organic chemistry
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.