Back to Search
Start Over
A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy.
- Source :
-
Nature communications [Nat Commun] 2024 Aug 04; Vol. 15 (1), pp. 6608. Date of Electronic Publication: 2024 Aug 04. - Publication Year :
- 2024
-
Abstract
- The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Female
Reactive Oxygen Species metabolism
Prodrugs pharmacology
Prodrugs chemistry
Photochemotherapy methods
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Mice, Nude
Xenograft Model Antitumor Assays
Tumor Microenvironment drug effects
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Breast Neoplasms pathology
Nuclear Proteins metabolism
Matrix Metalloproteinase 2 metabolism
Mice, Inbred BALB C
Neoplasms drug therapy
Neoplasms metabolism
Neoplasms pathology
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Bromodomain Containing Proteins
Proteolysis drug effects
Nanoparticles chemistry
Transcription Factors metabolism
Cell Cycle Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39098906
- Full Text :
- https://doi.org/10.1038/s41467-024-50735-w