TPGS-Transferrin-Conjugated Carvacrol-Loaded pH-Responsive Polydopamine Nanoconjugate: A Structure-Property Interplay Emphasizing Estrogen Receptor Positive Breast Cancer Cell and Involving In Vitro and In Vivo Toxicity Assessment Studies in Experimental Models.

Despite the antineoplastic potential of carvacrol (CVC), a plant-derived essential oil, it confronts several challenges related to solubility, biocompatibility, and lower cytotoxicity. To address these challenges, pH-controlled carvacrol-loaded polydopamine (PDA) nanoparticle conjugated to TPGS (d-α-tocopheryl polyethene glycol 1000 succinate)-transferrin moiety was fabricated to develop a promising breast cancer therapeutic agent. Characterization of the synthesized CVC-PDA-TPGS-Tf nanoconjugate was validated through several techniques. The CVC-PDA-TPGS-Tf nanoconjugate exhibited high encapsulation capacity (74.69±7.3%), sustained release kinetics, and rapid cellular internalization capability. Cytotoxicity, surface morphological changes, chromatin condensation, flow cytometric cell cycle arrest, DNA strand breakage, generation of intracellular reactive oxygen species, alteration of mitochondrial membrane potential, quantification of stages of apoptosis, and cytoskeleton deformation were investigated in estrogen-sensitive breast cancer MCF-7 cells to scrutinize the possibility of programmed cell death induction by the carvacrol nanoconjugate. The findings of the experiments validated the provocation of the fabricated CVC-PDA-TPGS-Tf nanoconjugate behind the oxidative assault-mediated apoptotic events in MCF-7 cells. To make a more suitable breast cancer therapeutic agent, it was essential to explore the overall biocompatibility and potential systemic toxicity of the fabricated nanoconjugate in both cellular and animal models. CVC-PDA-TPGS-Tf NPs treatment to Artemia nauplii and human lymphocytes was safe, and no significant cytotoxicity and oxidative stress were exhibited in the invitro cellular toxicity study. The nanoconjugate displayed no systemic toxicity and histoarchitectural alterations after repeated 28-day intraperitoneal administration at a dose of 100 mg/kg body weight in Swiss albino female mice, enhancing the biocompatibility and antineoplastic potential of carvacrol.