Glutathione-Scavenging Nanoparticle-Mediated PROTACs Delivery for Targeted Protein Degradation and Amplified Antitumor Effects

by Selleckchem | Aug 09 2023

PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin-proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano-PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano-PROTACs are developed by encapsulating PROTACs in glutathione (GSH)-responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano-PROTAC, nanoengineered BRD4 degrader ARV-771, improves BRD4 protein degradation and decreases the downstream oncogene c-Myc expression. Benefiting from the GSH-scavenging ability to amply the c-Myc-related ferroptosis and cell cycle arrest, this ARV@PDSA Nano-PROTACs strategy shows superior anti-tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano-PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.

Comments:

The passage describes a strategy called Nano-PROTACs (PROteolysis TArgeting Chimeras) that aims to overcome some limitations of PROTACs, a class of therapeutic molecules that selectively degrade intracellular proteins. PROTACs work by utilizing the ubiquitin-proteasome system to degrade specific proteins of interest. However, their clinical applications are currently limited due to challenges in efficiently delivering these degraders to target cells and concerns about potential toxicity.

The Nano-PROTACs approach involves encapsulating PROTACs within nanoparticles made of a glutathione (GSH)-responsive poly(disulfide amide) polymeric (PDSA) material. This nanoengineering strategy aims to enhance the bioavailability of PROTACs and maximize their ability to degrade intracellular oncogenic proteins for the treatment of tumors.

The researchers demonstrated the efficacy of the Nano-PROTACs strategy using a specific nanoengineered BRD4 degrader called ARV-771, which is encapsulated in ARV@PDSA nanoparticles. They showed that this Nano-PROTAC improved the degradation of the BRD4 protein and reduced the expression of the downstream oncogene c-Myc. The Nano-PROTACs took advantage of the ability of GSH to scavenge c-Myc-related ferroptosis (a type of regulated cell death) and induce cell cycle arrest. These effects led to superior anti-tumor efficacy with low-dose administration and demonstrated good biocompatibility in vivo.

Overall, this study highlights the potential of the Nano-PROTACs strategy to effectively target and degrade disease-associated proteins, offering a promising approach for the treatment of various diseases. By using nanoengineering techniques to enhance the delivery and bioavailability of PROTACs, this strategy may overcome some of the limitations currently associated with PROTAC-based therapies.