Pro-ATO/Allicin Liposomes for Dual-Pathway Targeting of p53-Mutant Tumors

Area of Science:

• Oncology
• Nanomedicine
• Molecular Biology

Background:

• Mutations in the tumor suppressor p53 are common in lung cancer, leading to DNA damage response (DDR) disruption and therapeutic resistance.
• Current treatments like arsenic trioxide (ATO) have limitations in selectivity and toxicity, while ATR inhibitors like allicin face stability and bioavailability issues.

Purpose of the Study:

• To develop a liposomal nanomedicine (AsAcP@LP) for co-delivering pro-ATO and allicin to combat p53-mutant lung cancers.
• To integrate mutant p53 reactivation with ATR-targeted synthetic lethality for improved therapeutic outcomes.

Main Methods:

• Formulation of liposomal nanomedicine (AsAcP@LP) co-delivering pro-ATO (As5+) and allicin.
• Evaluation of drug stability, pharmacokinetics, tumor accumulation, and in vivo antitumor efficacy.
• Assessment of p53 reactivation, ATR inhibition, and apoptosis induction.

Main Results:

• AsAcP@LP demonstrated improved drug stability, pharmacokinetics, and tumor accumulation, while masking allicin's odor.
• Tumor-specific release led to redox activation of As5+ to As3+, enabling selective p53 reactivation and ATR inhibition.
• The nanomedicine induced H2S-amplified apoptosis, showing synergistic antitumor efficacy with favorable tolerability.

Conclusions:

• AsAcP@LP represents a rational nanotherapeutic strategy for p53-mutant cancers.
• The combined approach of mutant p53 reactivation and synthetic lethality offers a promising avenue for cancer treatment.