In Vitro Evaluation of Cytotoxicity, Angiogenic Activity and Ex vivo Evaluation of Hemocompatibility of mPLGA-PEG Nanoparticles Encapsulating CDC42 Inhibitor (CASIN)

Abstract

Osteoporosis is a major cause of fragility fractures, especially in the elderly, where progressive loss of bone tissue causes serious clinical complications and considerably delays bone healing. Against osteoporosis, targeting key molecular regulators that control bone cell activity can enhance bone regeneration. Thus, according to the previous research inhibiting the small GTPase Cdc42 through Cdc42 activity-specific inhibitor (CASIN) has been shown to reduce osteoclast-mediated bone resorption, stimulate osteoblast driven bone formation, and enhance bone fracture healing. Despite therapeutic advantages, CASIN exhibits poor bioavailability and retention time in the bloodstream, which restricts direct clinical applications. To address such limitations, biodegradable and biocompatible nanoparticles based on poly(lactic-co-glycolic acid) – methoxy - polyethylene glycol (mPLGA-PEG) were chosen for controlled drug release with a potential for specific therapeutic action at the bone site.

This project evaluates mPLGA-PEG nanoparticles encapsulating the Cdc42 inhibitor (CASIN) as a potential new drug delivery system against osteoporotic fractures. Preclinical evidence links elevated Cdc42 activity to age-related bone loss and impaired mesenchymal stem/progenitor cell (MSPC) function, while Cdc42 inhibition restores cytoskeletal organization and increases bone volume in animal models. Building on these findings and previous research of Dr. Umbayev from NLA lab showing high encapsulation efficiency and stability of CASIN-loaded mPLGA-PEG nanoparticles, the biocompatibility of targeted nanoparticles will be assessed by evaluating angiogenic, cytotoxic potential in vitro, and ex vivo hemolytic activity. This approach may address the current gap in safe and effective delivery methods of Cdc42 inhibitor to bone fractures to accelerate bone repair in osteoporosis using nanotechnology therapy.