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

• Published in: Theranostics Vol. 11; no. 14; pp. 6833 - 6846
• Main Authors: Yan, Siqi, Yan, Jin, Liu, Dan, Li, Xiang, Kang, Qianyan, You, Weiming, Zhang, Jinghua, Wang, Lei, Tian, Zhiqi, Lu, Wuyuan, Liu, Wenjia, He, Wangxiao
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01-01-2021; Ivyspring International Publisher
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding sites; Cancer; Cancer therapies; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; Chemical Engineering - methods; Gold - chemistry; Humans; Hydrogen-Ion Concentration; Imidazoles - chemistry; Mice; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Peptides; Peptides - administration & dosage; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Proteins; Proteolysis; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism; R&D; Research & development; Research Paper; Retina; Retinoblastoma; Retinoblastoma - drug therapy; Retinoblastoma - metabolism; Sulfhydryl Compounds - chemistry; Tumor Protein p73 - metabolism; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; Supermolecule; Anti-cancer therapy; Protein targeted degradation; Peptide; p53
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.59020

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.
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.
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.
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.