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Research Article

A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy

Qingrong Li1,§Xiaoyuan Yang1,§Mengqiao Zhao2Xuelin Xia1Wenhui Gao1Wei Huang1( )Xiaoxia Xia2( )Deyue Yan1( )
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China

§ Qingrong Li and Xiaoyuan Yang contributed equally to this work.

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Graphical Abstract

A self-assembled affibody-proteolysis targeting chimeras (PROTAC) conjugate nanomedicine (ZHER2:342-MZ1 APCN) is prepared for cancer targeted therapy with excellent antitumor efficacy and good biosafety. Via the human epidermal growth factor receptor 2 (HER2) -mediated endocytosis, ZHER2:342-MZ1 APCN can be efficiently internalized by HER2-positive ovarian cancer cells and rapidly release PROTAC MZ1 to induce bromodomain-containing protein 4 (BRD4) degradation, leading to apoptosis of cancer cells and inhibition of tumor growth.

Abstract

Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody ZHER2:342 (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic ZHER2:342-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (ZHER2:342-MZ1 APCN) in water. Upon the excellent targeting property of ZHER2:342 and HER2 receptor-mediated endocytosis, ZHER2:342-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively in vitro. Under the intracellular high level of glutathione (GSH), ZHER2:342-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, ZHER2:342-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy in vivo for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy.

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Nano Research
Pages 9954-9964
Cite this article:
Li Q, Yang X, Zhao M, et al. A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy. Nano Research, 2024, 17(11): 9954-9964. https://doi.org/10.1007/s12274-024-6974-x
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Received: 01 June 2024
Revised: 12 August 2024
Accepted: 19 August 2024
Published: 07 September 2024
© Tsinghua University Press 2024
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