Rational Design of a Bioconjugated Antitumor Peptide with Tumor-Selective Targeting and Microenvironment-Responsive
Chunlai Feng1,2, Wen Deng3, Min Cai3
1School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu Province, China. feng@ujs.edu.cn.
Objective:
Bioactive peptides derived from natural or synthetic sources have shown significant potential for cancer therapy; however, their clinical application is often limited by poor tumor selectivity and systemic toxicity. In this work, we aim to develop a multifunctional antitumor peptide with enhanced tumor- targeting capability and therapeutic efficacy.
Methods:
A cationic antimicrobial peptide (AMP, (KKWW)2 K-NH2) was chemically modified via cysteine-mediated conjugation with 4-vinylphenylboronic acid, yielding the phenylboronic acid-conjugated AMP (PBA-AMP). Molecular dynamics (MD) simulations were performed to evaluate peptide-membrane interactions. Cellular uptake, cytotoxicity, and in vivo tumor-targeting and antitumor efficacy were assessed using MCF-7 cells and 4T1 tumor-bearing mice.
Results:
MD simulations demonstrated that PBA-AMP exhibited rapid and stable binding to tumor cell membranes, maintaining consistent membrane interactions over a 50 ns simulation. Cellular studies revealed enhanced cellular uptake and increased cytotoxicity of PBA-AMP against MCF-7 breast cancer cell line (IC50 = 38.46 μM) compared to naive AMP (IC50 = 110 μM). In vivo imaging confirmed selective and prolonged tumor accumulation of PBA-AMP. Treatment with PBA-AMP significantly suppressed tumor growth in 4T1 tumor-bearing mice without observable systemic toxicity.
Conclusions:
This study presents a rational design strategy for engineering tumor-selective, microenvironment-responsive therapeutic peptides. PBA-AMP represents a promising candidate for targeted cancer therapy, offering improved efficacy and reduced off-target effects.
Insights
Researchers developed a novel phenylboronic acid-conjugated antimicrobial peptide (PBA-AMP) for enhanced cancer therapy. This targeted peptide shows improved tumor selectivity, increased efficacy, and reduced toxicity in preclinical models, offering a promising new avenue for antitumor treatments.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Toxicology
- Oncology
Background:
- Bioactive peptides show promise in cancer therapy but suffer from poor tumor selectivity and systemic toxicity.
- Developing peptides with enhanced tumor-targeting capabilities is crucial for clinical application.
Purpose of the Study:
- To engineer a multifunctional antitumor peptide with improved tumor selectivity and therapeutic efficacy.
- To create a phenylboronic acid-conjugated antimicrobial peptide (PBA-AMP) for targeted cancer treatment.
Main Methods:
- Chemical modification of a cationic antimicrobial peptide (AMP) with 4-vinylphenylboronic acid.
- Molecular dynamics simulations to assess peptide-membrane interactions.
- In vitro cellular uptake and cytotoxicity assays (MCF-7 cells).
- In vivo tumor targeting, antitumor efficacy, and toxicity studies (4T1 tumor-bearing mice).
Main Results:
- PBA-AMP demonstrated rapid, stable binding to tumor cell membranes in simulations.
- Enhanced cellular uptake and increased cytotoxicity of PBA-AMP against MCF-7 cells (IC50 = 38.46 μM) compared to native AMP (IC50 = 110 μM).
- In vivo studies showed selective, prolonged tumor accumulation and significant tumor growth suppression with no observable systemic toxicity.
Conclusions:
- A rational design strategy for tumor-selective, microenvironment-responsive therapeutic peptides was presented.
- PBA-AMP is a promising candidate for targeted cancer therapy, exhibiting improved efficacy and reduced off-target effects.
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