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Two-in-one nanoparticle platform induces a strong therapeutic effect of targeted therapies in P-selectin-expressing
Shani Koshrovski-Michael1, Daniel Rodriguez Ajamil1, Pradip Dey1,2
1Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Abstract:
Combined therapies in cancer treatment aim to enhance antitumor activity. However, delivering multiple small molecules imposes challenges, as different drugs have distinct pharmacokinetic profiles and tumor penetration abilities, affecting their therapeutic efficacy. To circumvent this, poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-based nanoparticles were developed as a platform for the codelivery of synergistic drug ratios, improving therapeutic efficacy by increasing the percentage of injected dose reaching the tumor. Nonetheless, extravasation-dependent tumor accumulation is susceptible to variations in tumor vasculature; therefore, PLGA-PEG was modified with sulfates to actively target P-selectin-expressing cancers. Here, we show the potential of our platform in unique three-dimensional (3D) in vitro and in vivo models. The P-selectin-targeted nanoparticles showed enhanced accumulation in 3D spheroids and tissues of P-selectin-expressing BRAF-mutated melanomas and BRCA-mutated breast cancers, resulting in superior in vivo efficacy and safety. This nanoplatform could advance the codelivery of a plethora of anticancer drug combinations to various P-selectin-expressing tumors.
Insights
This study developed targeted nanoparticles for combined cancer therapy, improving drug delivery to tumors. The P-selectin-targeted nanoplatform demonstrated enhanced efficacy and safety in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Combined cancer therapies enhance antitumor activity but face challenges in delivering multiple drugs due to differing pharmacokinetics and tumor penetration.
- Conventional nanoparticle drug delivery relies on passive extravasation, which can be inconsistent due to tumor vasculature variability.
Purpose of the Study:
- To develop a P-selectin-targeted nanoplatform for enhanced codelivery of synergistic anticancer drug ratios.
- To improve therapeutic efficacy by increasing drug accumulation in P-selectin-expressing tumors.
Main Methods:
- Poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles were modified with sulfates for active targeting.
- The platform was evaluated in three-dimensional (3D) in vitro spheroid models and in vivo cancer models.
- Nanoparticle accumulation and therapeutic efficacy were assessed in P-selectin-expressing melanomas and breast cancers.
Main Results:
- P-selectin-targeted nanoparticles showed enhanced accumulation in 3D spheroids and tissues of targeted cancers.
- The nanoplatform demonstrated superior in vivo efficacy and safety compared to non-targeted approaches.
- Successful targeting was observed in BRAF-mutated melanomas and BRCA-mutated breast cancers.
Conclusions:
- The developed P-selectin-targeted nanoplatform effectively enhances the codelivery of anticancer drugs to specific tumors.
- This approach offers a promising strategy for improving the efficacy and safety of combined cancer therapies.
- The nanoplatform has the potential for broad application in treating various P-selectin-expressing cancers.
