Unique Polyester-Based Biodegradable Multiarm Nano-Carrier for Cancer Cell Specific Mitochondrial Delivery of Chemotherapeutics

Biodegradable polymeric nanocarriers hold significant potential for various biomedical applications, enabling the targeted and controlled delivery of drugs and bioactive molecules. In this context, pendant-functionalized polycaprolactone has garnered tremendous attention over the past few decades. Herein, we developed a mitochondria-targeted polycaprolactone-based polyprodrug, TPP PCL CPT PEG BTN, for the site-specific delivery of camptothecin (CPT). The design incorporates triphenylphosphonium (TPP⁺) and tertiary amine moieties for mitochondrial targeting, biotin (BTN) for receptor-mediated uptake, and CPT as a chemotherapeutic payload. The polymer was synthesized via ring-opening polymerization and alkyne-azide click chemistry and self-assembled into uniform spherical nanoaggregates (∼117 ± 20 nm) as confirmed by DLS, TEM, and SEM. Confocal microscopy demonstrated efficient cellular uptake and mitochondrial localization in HeLa cells. Cytotoxicity assays revealed high selective anticancer activity (IC₅₀ = 8 μg/mL) with minimal toxicity toward normal HaCaT cells. These findings suggest that TPP PCL CPT PEG BTN is a promising mitochondria-targeted nanocarrier for precision cancer chemotherapy.