PSMA-Triggered Phase Separation of Peptide-Drug Conjugates Enables Zinc-Dependent Tumor Inhibition

Area of Science:

• Bioconjugation Chemistry
• Nanomedicine
• Cancer Therapeutics

Background:

• Peptide-drug conjugates (PDCs) show promise for targeted tumor therapy but face challenges like rapid clearance and poor drug release control.
• Next-generation PDCs require spatiotemporal regulation and enhanced pharmacological activity for improved therapeutic efficacy.

Purpose of the Study:

• To develop a structurally adaptive PDC platform, LE-HOA, utilizing cascade reconstruction induced by liquid-liquid phase separation (LLPS).
• To enhance drug stability, control drug release kinetics, and improve the drug-tumor interface for targeted cancer therapy.

Main Methods:

• Constructed LE-HOA by linking a tumor-targeting peptide (LE) with 4-(hydroxyamino)-4-oxobutanoic acid (HOA).
• Investigated self-assembly into nanomicelles under physiological conditions and disassembly/LLPS under PSMA induction.
• Evaluated in vitro and in vivo efficacy, including pharmacological signaling, tumor suppression, and biosafety.

Main Results:

• LE-HOA self-assembled into stable nanomicelles, enhancing circulation stability.
• PSMA induction triggered HOA release and LLPS, forming nanofibers that expanded the drug-tumor recognition interface.
• Demonstrated sustained pharmacological signaling, effective tumor suppression, and good biosafety in both in vitro and in vivo models.

Conclusions:

• The LE-HOA platform offers a novel strategy for PDC therapeutics by integrating intelligent response and dynamic phase behavior.
• This approach addresses limitations in current PDCs, enabling enhanced lesion-targeted action and improved therapeutic outcomes.
• The findings suggest a promising new direction for developing advanced drug delivery systems for cancer treatment.