A new short pH-responsive anticancer peptide derived by intramolecular charge shielding strategy

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• pH-responsive anticancer peptides (ACPs) offer selective tumor targeting.
• Limitations include narrow therapeutic index, poor stability, and long sequences.

Purpose of the Study:

• To design and evaluate short, pH-responsive ACPs with enhanced safety and stability.
• To overcome limitations of existing ACPs through intramolecular charge shielding.

Main Methods:

• Construction of histidine-rich peptide LH with intramolecular charge shielding.
• Synthesis and characterization of novel short ACPs, including 2E-K.
• In vitro evaluation of antitumor activity, cell death mechanisms, and selectivity.
• In vivo efficacy and toxicity studies compared to PTX.

Main Results:

• The peptide 2E-K demonstrated significant pH-dependent antitumor activity.
• 2E-K showed a 14.5-fold increase in therapeutic selectivity and a 3.6-fold longer serum half-life compared to LH.
• Acid-activated 2E-K induced rapid membrane damage in tumor cells.
• In vivo studies confirmed 2E-K's excellent antitumor efficacy and low toxicity compared to PTX.

Conclusions:

• The novel design strategy effectively created short, stable, and selective pH-responsive ACPs.
• 2E-K represents a promising alternative drug candidate for cancer treatment.
• This work paves the way for developing advanced ACPs with improved therapeutic profiles.