Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

Abstract

PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

“…Drug-like properties may be improved by cell permeable precursors or by computer aided drug design softwares [ 51 , 55 ]. Clinical delivery and metabolic stability may be advanced by application of prodrug PROTACs, antibody-drug conjugates, folate-PROTACs, aptamer-PROTAC conjugates and nanoparticle based PROTACs to penetrate deep into tumors [ 56 , 65 , 66 , 67 , 68 , 109 , 222 ].…”

“…Although in vivo data is missing, Cer/Pom-PEG@GNPs as a nano-based drug carrier promises prolonged circulation and specific delivery of drugs to tumor regions, and can be beneficial in patients resistant to ALK kinase inhibitors [ 65 ]. Furthermore, Yu and colleagues reported polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumor specific targeted degradation [ 66 ]. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumor microenvironments.…”

“…The POLY-PROTAC nanoparticles carry azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumor region. Tumor specific BRD4 depletion via the POLY-PROTAC nanoplatform combined with photodynamic therapy resulted in tumor regression in a mouse xenograft model of MDA-MB-231 breast cancer [ 66 ]. For the successful translation of the so-called nanoPROTACs into the clinical setting, safety analysis and optimization of a chemical and manufacturing control procedure are required [ 67 ].…”

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

“…In addition, Yu et al used this in situ bioorthogonal tumor targeting strategy to design a poly-PROTAC (POLY-PROTAC) nanoplatform for targeted degradation of BRD4, which improved tumor selectivity and precise delivery of proteolysis targeting chimeras (PROTACs). 141 DBCO-modified POLY-PROTAC achieved selective tumor targeting and retention by bioorthogonal reaction with N 3 -modified self-assembled micelles that enter the tumor beforehand, resulting in an approximately 1.9-fold increase in nanoparticle accumulation in the tumor compared to the group without bioorthogonal reaction. Yang et al also constructed an in situ self-assembled drug reservoir using bioorthogonal reactions between cyanide of cysteine (Cys) and 2-cyanobenzothiazole (CBT) for the resident and sustained release of multiple drugs, improving the performance of a cocktail of chemoimmunotherapies.…”

A Perspective on Newly Emerging Proteolysis-Targeting Strategies in Antimicrobial Drug Discovery

“…Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins, especially to cross the dense bacterial cell wall. The incorporation of PROTAC-like molecules with nanoparticles will precisely take these degrader molecules to the diseased site, where the off-target effects and the lower cell permeability could be greatly minimized [ 70 ]. Though there are 600 E3 ligases encoded in the human genome, only 4 of them are targeted in PROTAC-based degradation.…”