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Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma
Aviram Mizrachi1,2, Yosi Shamay3, Janki Shah3
1Head and Neck Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Abstract:
Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas.
Insights
Targeted nanoparticles deliver PI3Kα inhibitor BYL719 specifically to tumors, enhancing efficacy and reducing side effects in head and neck cancer. This novel strategy improves treatment safety and effectiveness.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- PIK3CA gene alterations are common in head and neck squamous cell carcinomas.
- PI3Kα inhibitors show anti-cancer potential but are limited by dose-limiting toxicities like hyperglycemia.
- BYL719 is a PI3Kα inhibitor in clinical development for solid tumors.
Purpose of the Study:
- To evaluate the efficacy, specificity, and safety of targeted delivery of the PI3Kα inhibitor BYL719 using P-selectin-targeted nanoparticles.
- To investigate if nanoparticle encapsulation can enhance BYL719 accumulation in tumors and improve therapeutic outcomes.
- To assess the potential of this targeted delivery system to mitigate dose-limiting metabolic side effects.
Main Methods:
- BYL719 was encapsulated into P-selectin-targeted nanoparticles.
- The targeted nanoparticles were administered to assess drug accumulation in the tumor microenvironment.
- Tumor growth inhibition and radiosensitization were evaluated.
- Acute and chronic metabolic side effects were monitored.
Main Results:
- P-selectin-targeted nanoparticles achieved specific accumulation of BYL719 in the tumor.
- A sevenfold lower dose of BYL719 via nanoparticles resulted in tumor growth inhibition and radiosensitization compared to oral administration.
- Nanoparticle delivery abrogated both acute and chronic metabolic side effects associated with BYL719 treatment.
Conclusions:
- Targeted delivery of BYL719 using P-selectin nanoparticles offers a promising strategy for head and neck squamous cell carcinomas.
- This approach enhances therapeutic efficacy and significantly mitigates dose-limiting toxicities.
- Nanoparticle-mediated drug delivery represents a novel method to improve the safety and effectiveness of PI3Kα inhibitors in cancer treatment.
