Theranostics 2021; 11(14):6833-6846. doi:10.7150/thno.59020

Research Paper

A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity

Siqi Yan1,2*, Jin Yan3✉*, Dan Liu1*, Xiang Li4*, Qianyan Kang2, Weiming You3, Jinghua Zhang5, Lei Wang6, Zhiqi Tian7, Wuyuan Lu8✉, Wenjia Liu6✉, Wangxiao He1,6✉

1. Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
2. Ophthalmology Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
3. National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
4. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
5. School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
6. Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
7. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, 45267 OH, USA.
8. School of Basic Medicine, Fudan University, Shanghai 20433, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Yan S, Yan J, Liu D, Li X, Kang Q, You W, Zhang J, Wang L, Tian Z, Lu W, Liu W, He W. A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity. Theranostics 2021; 11(14):6833-6846. doi:10.7150/thno.59020. Available from https://www.thno.org/v11p6833.htm

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Abstract

As alternatives to small-molecular proteolysis-targeting chimeras (PROTAC), peptide-based molecular glues (MG) are a broad range of dual-functional ligands that simultaneously bind with targetable proteins and E3 ligases by mimicking proteinprotein interaction (PPI) partners.

Methods: Herein, we design a peptide-derived MG to target a tumor-driving protein, MDMX, for degradation, and nanoengineered it into a supramolecular gold(I)-thiol-peptide complex (Nano-MP) to implement the proteolysis recalcitrance, cellular internalization, and glutathione-triggered release. To optimize the tumor targeting, a pH-responsive macromolecule termed polyacryl sulfydryl imidazole (PSI) was synthesized to coat Nano-MP.

Results: As expected, Nano-MP@PSI induced the MDMX degradation by ubiquitination and subsequently restored the anti-cancer function of p53 and p73. Nano-MP@PSI revealed potent anti-cancer activities in an orthotopic xenograft mouse model of retinoblastoma by intraocular injection and a patient-derived xenograft model of malignant pancreatic cancer by systemic injection, while maintaining a favorable safety profile and showing a highly favorable clearable profile of excretion from the living body.

Conclusion: Collectively, this work not only provided a clinically viable paradigm for the treatment of a wide variety of tumors by multiple administration types, but, more importantly, it bridged the chasm between peptides and PROTACs, and likely reinvigorated the development of peptide-derived proteolysis-targeting chimeras for a great variety of diseases.

Keywords: Protein targeted degradation, Peptide, p53, Anti-cancer therapy, Supermolecule