2. Academic Validation
  3. Near-Infrared-Activatable PROTAC Nanocages for Controllable Target Protein Degradation and On-Demand Antitumor Therapy

Near-Infrared-Activatable PROTAC Nanocages for Controllable Target Protein Degradation and On-Demand Antitumor Therapy

  • J Med Chem. 2023 Jun 6. doi: 10.1021/acs.jmedchem.3c00587.
Qi He 1,  Liming Zhou 2,  Daxin Yu 1,  Ren Zhu 3,  Yue Chen 2,  Mingbo Song 1,  Xintong Liu 1,  Yixian Liao 1,  Tong Ding 1,  Wenpei Fan 2,  Wenying Yu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
  • 2 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 3 Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Hubei Engineering Research Center for Advanced Fine Chemicals, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, 206 1st Rd Optics Valley, East Lake New Technology Development District, Wuhan, Hubei 430205, People's Republic of China.
PMID: 37279091 DOI: 10.1021/acs.jmedchem.3c00587
Abstract

As a novel protein knockdown tool, proteolysis targeting chimeras (PROTACs) can induce potent degradation of target proteins by hijacking E3 ubiquitin ligases. However, the uncontrollable protein disruption of PROTACs is prone to cause "off-target" toxicity after systemic administration. Herein, we designed a photocaged-PROTAC (phoBET1) and loaded it in UCNPs-based mesoporous silica nanoparticles (UMSNs) to construct a NIR light-activatable PROTAC nanocage (UMSNs@phoBET1) for controllable target protein degradation. Upon NIR light (980 nm) irradiation, UMSNs@phoBET1 nanocages could be activated to release active PROTAC via a controlled pattern for degrading bromodomain-containing protein 4 (BRD4) and inducing MV-4-11 Cancer cell Apoptosis. In vivo experiments demonstrated that UMSNs@phoBET1 nanocages were capable of responding to NIR light in tumor tissues to achieve BRD4 degradation and effectively suppress tumor growth. This NIR light-activatable PROTAC nanoplatform compensates for the current shortcomings of short-wavelength light-controlled PROTACs and presents a paradigm for the precise regulation of PROTACs in living tissues.

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