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Enzyme-Instructed Nanofibrous Assemblies Enable Targeted PROTAC Release for Cancer Therapy
Yuchen Yang1,2, Chunrong Yang1, Zongliang Fu3
1New Cornerstone Science Laboratory, Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, China.
Abstract:
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for the selective degradation of oncoproteins, offering significant potential in cancer therapy, yet their clinical translation is impeded by the inherent limitations, including high hydrophobicity, poor cellular permeability, and inadequate tumor-targeting efficiency. To address these challenges, we developed a rationally engineered peptide conjugate, Nap-Lys(ARV-771)-Tyr(H2PO3)-Phe-Phe-OH (NapYp-ARV), to enhance the bioavailability and therapeutic efficacy of PROTACs through sequential enzyme-instructed self-assembly (EISA) and activation. Upon intratumoral phosphatase-mediated dephosphorylation, NapYp-ARV self-assembles into nanofibers that enhance tumor accumulation. Following cellular internalization, carboxylesterase-catalyzed hydrolysis liberates the PROTAC payload ARV-771, inducing potent BRD4 degradation and consequent apoptosis. In vivo, NapYp-ARV administration achieved higher tumor drug concentration than free ARV-771, driving robust protein degradation and tumor regression while maintaining hematological and histological safety. Collectively, this EISA-based delivery platform offers a versatile strategy to advance targeted PROTAC therapies.
Insights
This study introduces a novel peptide conjugate for enhanced cancer therapy. The new PROTAC delivery system improves tumor targeting and drug efficacy, offering a promising strategy for targeted protein degradation.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Delivery Systems
Background:
- Proteolysis-targeting chimeras (PROTACs) show promise for cancer therapy but face challenges like poor bioavailability and tumor targeting.
- Limitations include hydrophobicity, poor cell permeability, and inefficient tumor accumulation.
Purpose of the Study:
- To develop an engineered peptide conjugate (NapYp-ARV) to overcome PROTAC limitations.
- To enhance PROTAC bioavailability and therapeutic efficacy using enzyme-instructed self-assembly (EISA) and activation.
Main Methods:
- Designed NapYp-ARV, a peptide conjugate utilizing sequential EISA and activation.
- Investigated phosphatase-mediated dephosphorylation for self-assembly into tumor-accumulating nanofibers.
- Assessed carboxylesterase-catalyzed hydrolysis for PROTAC payload release and BRD4 degradation.
Main Results:
- NapYp-ARV self-assembled into nanofibers upon dephosphorylation, enhancing tumor accumulation.
- Intracellular hydrolysis released the PROTAC payload, inducing BRD4 degradation and apoptosis.
- In vivo studies showed increased tumor drug concentration, robust protein degradation, and tumor regression with good safety.
Conclusions:
- The EISA-based delivery platform effectively enhances PROTAC bioavailability and tumor targeting.
- This strategy offers a versatile approach to advance targeted PROTAC therapies for cancer.
- NapYp-ARV demonstrates significant potential for improving cancer treatment outcomes.
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