Targeted Delivery of Carvacrol via TPGS-Tf–Polydopamine Nanoconjugate Scaffold on TNBC Tumor Xenograft for Understanding In Vivo Tumor Dynamics and 3D Cancer Spheroid Model, Mimicking a Tumor Environment

Abstract

The high expression of transferrin receptors on the surface of cancer cells makes them a potential target for drug internalization, which has become a golden opportunity in targeted cancer therapy. Carvacrol, a naturally occurring phenolic compound present in essential oils, has attracted considerable attention for its pronounced anticancer activity against diverse human malignancies. Nevertheless, its therapeutic application in vivo is constrained by intrinsic physicochemical and pharmacokinetic limitations, including poor water solubility, suboptimal bioavailability, and rapid systemic elimination. To address these challenges, the present study highlights the fabrication of transferrin-targeted TPGS-conjugated carvacrol (CVC)-loaded polydopamine nanoparticles (CVC-PDA-TPGS-Tf NPs), with exploration of the antitumor efficacy of nanocarrier-mediated carvacrol, deploying a murine triple-negative breast cancer (TNBC) tumor xenograft model and a human TNBC three-dimensional (3D) spheroid model, as 3D cell culture technologies more thoroughly bear a resemblance to in vivo cell environments to accommodate improved precision in drug discovery. This work demonstrates the successful creation of nanoconjugate CVC-PDA-TPGS-Tf NPs (∼112 nm in size) and their thorough physicochemical characterization after synthesis. Intraperitoneal administration of CVC-PDA-TPGS-Tf NPs substantially inhibited tumor growth in the 4T1 xenograft model. Carvacrol effectively disintegrates MDA-MB-231 spheroids, illustrating a proportionately higher uptake of carvacrol nanoconjugates by these spheroids. The molecular docking studies also pinpointed the interaction of potential cancer biotargets with carvacrol in estrogen- and progesterone-receptor-positive breast cancer cells, in addition to its mentioned therapeutic efficiency against TNBC. In conclusion, these findings support CVC-PDA-TPGS-Tf as a promising platform for TNBC and potentially hormone receptor-positive breast cancers, warranting further mechanistic and translational studies.