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Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy.
- Source :
-
Signal transduction and targeted therapy [Signal Transduct Target Ther] 2024 Oct 18; Vol. 9 (1), pp. 275. Date of Electronic Publication: 2024 Oct 18. - Publication Year :
- 2024
-
Abstract
- PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Mice
Animals
Cyclin-Dependent Kinase 6 genetics
Cathepsin B metabolism
Cathepsin B genetics
Cell Line, Tumor
Tumor Microenvironment drug effects
Xenograft Model Antitumor Assays
Colorectal Neoplasms drug therapy
Colorectal Neoplasms pathology
Colorectal Neoplasms genetics
Nanoparticles chemistry
Proteolysis drug effects
Cyclin-Dependent Kinase 4 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2059-3635
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Signal transduction and targeted therapy
- Publication Type :
- Academic Journal
- Accession number :
- 39419977
- Full Text :
- https://doi.org/10.1038/s41392-024-01983-1