Enhanced Delivery of Regorafenib in Tpgs-Based Nanomicelles Incorporated Into Hyaluronic Acid-Methylcellulose Hydrogel Against Colon Cancer Cells Publisher



Shahriari MH ; Shaban M ; Salmani H ; Malekkhatabi A ; Salehi Z ; Akrami M
Source: Journal of Drug Delivery Science and Technology Published:2026

Abstract

Regorafenib (REGO), a multi-kinase inhibitor approved for metastatic colorectal cancer, suffers from poor aqueous solubility and significant systemic toxicity that limit its therapeutic efficacy. This study describes a drug delivery system integrating REGO-loaded D-α-tocopheryl polyethylene glycol 1000 succinate nanomicelles (TPGS) into a thermoresponsive hyaluronic acid (HA)-methylcellulose (MC) hydrogel (REGO-TPGS/HA-MC) for enhanced colon cancer therapy. The TPGS micelles exhibited optimal physicochemical properties with a mean diameter of 20.34 ± 4.21 nm, polydispersity index of 0.278 ± 0.033, zeta potential of −6.13 ± 1.12 mV, and drug loading efficiency of 65.37 ± 7.75% corresponding to 130 ± 14 μg/mL REGO concentration. The hydrogel demonstrated interconnected porous microstructure and thermosensitive gelation at 37 °C within 100 s. In vitro release studies revealed controlled biphasic kinetics with cumulative release of 90.46 ± 3.82% and 87.25 ± 4.46% over 24 h for nanomicelles and hydrogel formulations, respectively. The delivery systems demonstrated superior cytotoxicity against SW480 colon cancer cells with IC50 values of 186.5 ng/mL for nanomicelles and 193.1 ng/mL for hydrogel, representing approximately 450-fold improvement compared to free REGO. Cellular uptake studies using curcumin (CUR) as a fluorescent probe revealed 98.1% internalization efficiency for nanomicelles and 92.9% for the hydrogel formulation. Gene expression analysis revealed formulation-dependent transcriptional patterns consistent with apoptotic progression: free REGO induced global mRNA suppression (BAX 0.17-fold, Caspase-3 0.55-fold, Caspase-8 0.51-fold) characteristic of advanced apoptotic commitment, while the hydrogel formulation maintained early-phase apoptotic signaling with Caspase-3 upregulation (1.74-fold) reflecting sustained drug release kinetics. In vivo biodistribution imaging demonstrated superior subcutaneous retention of the hydrogel formulation over 2 h compared to rapid clearance of nanomicelles alone. Mucin penetration studies confirmed enhanced permeation capability with time-dependent increases in fluorescence intensity for both formulations. These findings demonstrate that the REGO-TPGS/HA-MC platform addresses REGO's pharmaceutical limitations through enhanced solubility, controlled release, and localized delivery, warranting further investigation for clinical translation in colorectal cancer management. Copyright © 2026. Published by Elsevier B.V.