Discovery of novel HER2 targeting peptide-camptothecin conjugates with effective suppression for selective cancer...

Area of Science:

• Oncology
• Pharmacology
• Bioconjugation Chemistry

Background:

• Peptide-drug conjugates (PDCs) offer targeted delivery of cytotoxic payloads to tumors.
• HER2 is a validated target in several human cancers, including breast and gastric.
• Previous work identified peptide P1 (NPNWGRSWYNQRFK) as a HER2-targeting moiety.

Purpose of the Study:

• To design and evaluate novel peptide-drug conjugates (PDCs) for HER2-targeted cancer therapy.
• To optimize the linker strategy for connecting the P1 peptide and the cytotoxic payload camptothecin (CPT).
• To assess the in vitro and in vivo efficacy and safety of the developed PDCs.

Main Methods:

• Synthesis of a series of PDCs by conjugating peptide P1 with camptothecin (CPT) using various linkers.
• In vitro cytotoxicity assays (IC50 determination) on HER2-positive cell lines (SK-BR-3, NCI-N87).
• In vivo antitumor activity and biosafety evaluation of the lead compound compared to CPT.

Main Results:

• The optimal PDC, designated Z8, demonstrated significant antitumor activity.
• Z8 exhibited potent in vitro efficacy with IC50 values of 1.04 ± 0.24 μM (SK-BR-3) and 1.91 ± 0.71 μM (NCI-N87).
• In vivo studies showed superior antitumor efficacy and enhanced biosafety for Z8 compared to the free drug CPT.

Conclusions:

• The novel peptide-drug conjugate Z8 exhibits promising HER2-targeted antitumor activity and improved safety profile.
• This study provides a novel strategy for the rational design and construction of effective peptide-drug conjugates for cancer treatment.
• Z8 represents a potential therapeutic candidate for HER2-positive malignancies.