Rational Design of a Bioconjugated Antitumor Peptide with Tumor-Selective Targeting and Microenvironment-Responsive...

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.