Biotin-Functionalized Multi-Stimuli-Responsive Polymeric Prodrug for Receptor-Mediated and Mitochondria-Targeted Codelivery of Camptothecin and Protocatechualdehyde

Abstract Triple-negative breast cancer (TNBC) remains difficult to treat because of limited molecular targets and multidrug resistance. Here, we develop CPB, a biodegradable poly(ε-caprolactone)-polymeric prodrug nanoplatform integrating biotin-mediated uptake, triphenylphosphonium- and quaternary-ammonium-driven mitochondrial targeting, redox-responsive thioether-linked camptothecin (CPT), and acid-labile imine-linked protocatechualdehyde (PCA). CPB self-assembles into physiologically stable nanoparticles (212 ± 5 nm; PDI 0.224) with minimal premature leakage. Biotin enhances sodium-dependent multivitamin transporter-mediated uptake by ≈ 1.5-fold, while combined pH, esterase, and redox stimuli trigger ≈92% CPT, ≈84% PCA release within 72 h. In MDA-MB-231 cells, CPB internalizes efficiently, preferentially accumulates in mitochondria, and amplifies mitochondrial reactive oxygen species generation via PCA. Consequently, CPB elicits potent antiproliferative activity (IC50 = 10 μg mL−1), negligible toxicity toward HEK-293 cells, and superior efficacy over free CPT and single-drug controls through synergistic CPT-induced nuclear DNA damage and PCA-mediated mitochondrial dysfunction, establishing a promising strategy for overcoming therapeutic resistance in aggressive and treatment-refractory, clinically relevant TNBC settings.