Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

  • Chem Sci. 2019 Dec 6;11(4):1132-1139. doi: 10.1039/c9sc04317a.
Dongdong Liu  1  2 ,  Zhe Miao  1 ,  Chengling Wu  1 ,  Fangfei He  1 ,  Peng Ren  3 ,  Shuo Bai  3 ,  Xingyu Jiang  1  2  4 ,  Yuan Gao  1  2
Affiliations
  • 1. CAS Center for Excellence in Nanoscience, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology Beijing 100190 P. R. China [email protected].
  • 2. Sino-Danish College, University of Chinese Academy of Sciences Beijing 100049 P. R. China.
  • 3. Institute of Process Engineering, Chinese Academy of Sciences Beijing 100190 P. R. China.
  • 4. Department of Biomedical Engineering, Southern University of Science & Technology Shenzhen 518055 Guangdong P. R. China.
PMID: 34084370 DOI: 10.1039/c9sc04317a
Abstract

Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with Anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the Cytoskeleton and sensitizes Cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated Cancer.

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