Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index

Area of Science:

• Oncology
• Nanomedicine
• Pharmacology

Background:

• Fibroblast growth factor receptor (FGFR) inhibitors are approved for specific cancers but cause dose-limiting toxicities.
• Developing targeted drug delivery systems can enhance efficacy and reduce side effects of FGFR inhibitors.

Purpose of the Study:

• To encapsulate FGFR inhibitors (ponatinib, PD173074, nintedanib) into nanoparticles and liposomes.
• To evaluate the formulations for improved tumor accumulation, specificity, and reduced toxicity.
• To assess the in vitro and in vivo efficacy of nanoencapsulated FGFR inhibitors.

Main Methods:

• Encapsulation of ponatinib, PD173074, and nintedanib into polylactic acid nanoparticles and liposomes.
• Characterization of formulations for size distribution and encapsulation efficiency.
• In vitro cytotoxicity assays (short-term and clonogenic) and in vivo studies in a murine osteosarcoma model.

Main Results:

• Liposomal formulations achieved appropriate encapsulation levels, unlike nanoparticles.
• Nanoencapsulation led to slower in vitro drug uptake and reduced short-term cytotoxicity.
• Liposomal FGFR inhibitors showed equal or greater long-term activity in clonogenic assays.
• Liposomal ponatinib significantly inhibited osteosarcoma tumor growth (60.4%) with reduced side effects in vivo.

Conclusions:

• Liposomal encapsulation is a promising strategy to enhance the therapeutic index of FGFR inhibitors.
• This approach can improve tumor-specific drug delivery and mitigate dose-limiting adverse effects.
• Liposomal FGFR inhibitors demonstrate potential for treating FGFR inhibitor-sensitive cancers like osteosarcoma.