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The Peptide-Drug Conjugate M1pep-Tasquinimod Ameliorates Acute Pancreatitis via Selectively Clearing M1-like
Fangyue Guo1, Xufeng Tao2, Zhiwen Zhai3
1Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Abstract:
M1-like macrophages dominate local and systemic inflammatory response progression in acute pancreatitis (AP). The development of strategies to target pro-inflammatory M1-like macrophages in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of AP. Peptide-drug conjugates (PDCs), which are emerging second-generation conjugate drugs, have quickly become a new favorite in the field of targeted drug delivery due to their superior drug bioavailability, affinity, and stability. Tasquinimod (Tasq) is a specific inhibitor of S100A9 that is expressed mainly in M1-like macrophages during AP. Drug repositioning revealed that Tasq improved AP in a dose-dependent manner, but drug toxicity occurred at doses of 30 mg/kg. Therefore, we selected 2 specific M1-like macrophage-binding peptides (M1peps) by phage display technology and developed a novel PDC, M1pep-Tasq, by connecting M1peps to activated Tasq with a cleavable linker. Based on a mouse model of AP constructed by retrograde injection of sodium taurine cholate into the bile pancreatic duct and an M1-like macrophage polarization model induced by lipopolysaccharide + interferon-γ stimulation, we confirmed that M1pep-Tasq reduces the drug toxicity of Tasq and improves its efficacy by enhancing the targeting of Tasq to damaged organs in vivo and to M1-like macrophages in vitro. Furthermore, M1pep-Tasq effectively improves AP by inhibiting M1-like macrophage polarization by suppressing the S100A9-TLR4-MAPK pathway. Overall, we have developed a novel PDC, M1pep-Tasq, with promising applications in clinical settings to treat a range of inflammatory disorders by increasing the efficacy and reducing the toxicity of Tasq.
Insights
A novel peptide-drug conjugate, M1pep-Tasq, targets M1-like macrophages to treat acute pancreatitis (AP). This approach enhances drug efficacy and reduces toxicity, offering a promising therapy for inflammatory disorders.
Area of Science:
- Immunology
- Pharmacology
- Drug Delivery
Background:
- M1-like macrophages are key drivers of inflammation in acute pancreatitis (AP).
- Targeting these macrophages alongside existing therapies presents a significant clinical challenge.
- Tasquinimod (Tasq), an S100A9 inhibitor, shows therapeutic potential but suffers from dose-dependent toxicity.
Purpose of the Study:
- To develop a targeted drug delivery system for Tasquinimod (Tasq) to enhance its efficacy and reduce toxicity in acute pancreatitis (AP).
- To create a novel peptide-drug conjugate (PDC) for selective delivery to M1-like macrophages.
Main Methods:
- Selected M1-like macrophage-binding peptides (M1peps) using phage display technology.
- Developed a novel PDC, M1pep-Tasq, by conjugating M1peps to Tasq via a cleavable linker.
- Utilized a mouse model of AP and an in vitro M1-like macrophage polarization model.
Main Results:
- M1pep-Tasq demonstrated enhanced targeting of Tasq to damaged organs and M1-like macrophages.
- The novel PDC significantly reduced Tasq's toxicity while improving its therapeutic efficacy in AP models.
- M1pep-Tasq effectively inhibited M1-like macrophage polarization by suppressing the S100A9-TLR4-MAPK pathway.
Conclusions:
- M1pep-Tasq represents a promising novel peptide-drug conjugate for treating acute pancreatitis (AP).
- This targeted approach increases Tasq efficacy and reduces toxicity, with potential applications in various inflammatory disorders.
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