Apoptosis-Amplified Intracellular Paclitaxel Nanoparticle Formation Enhances Microtubule Aggregation and PANoptosis

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapeutics

Background:

• Paclitaxel's clinical use is hindered by dose-limiting toxicities and inefficient cellular delivery.
• Existing nanoformulations face challenges in achieving effective intracellular drug concentrations.
• Enhancing the anticancer efficacy of intracellular paclitaxel nanostructures requires novel strategies.

Purpose of the Study:

• To develop a paclitaxel conjugate that forms nanoparticles intracellularly, amplifying apoptosis for enhanced anticancer effects.
• To design a system leveraging caspase-3 activity for a self-amplifying nanoparticle formation loop.
• To investigate the potential of this strategy for improved tumor treatment.

Main Methods:

• Synthesis of a caspase-3-responsive peptide-paclitaxel conjugate (Ac-DEVDC(StBu)K(PTX)-CBT).
• Investigation of intracellular nanoparticle formation triggered by glutathione reduction and caspase-3 cleavage.
• Evaluation of in vitro anticancer activity, including cell cycle inhibition and induction of PANoptosis.
• Assessment of in vivo efficacy in orthotopic tumor models, measuring caspase-3 levels and survival rates.

Main Results:

• The conjugate self-assembled into paclitaxel nanoparticles intracellularly, forming an amplification loop.
• In vitro studies showed significant cell cycle inhibition, reduced phosphorylated YAP-1, and induced PANoptosis.
• In vivo studies demonstrated increased caspase-3 expression and prolonged survival compared to free paclitaxel.
• The mechanism involves cytoskeleton disruption and apoptosis amplification.

Conclusions:

• The developed paclitaxel conjugate effectively forms intracellular nanoparticles, amplifying apoptosis and enhancing therapeutic outcomes.
• This strategy offers a promising approach to overcome paclitaxel's limitations for improved cancer treatment.
• The self-amplifying nanoparticle formation loop presents a novel mechanism for boosting anticancer efficacy.