Novel biocompatible multifunctional porous magnetic nanoclusters for the targeted delivery of lenvatinib towards hepatocellular carcinoma†

Abstract

Hepatocellular carcinoma (HCC) is a very aggressive and deadly disease with a complicated tumor microenvironment (TME). Recently, lenvatinib (LEN) has shown effectiveness in the clinical treatment of HCC, but its limited solubility and serious adverse reactions must not be overlooked. Herein, we developed novel pluronic F127-decorated citric acid-capped, LEN-loaded porous magnetic nanoclusters (PF127/CA/LEN@pMNCs) for effective tumor targeting and toxicity reduction. PF127/CA/LEN@pMNCs were statistically optimized and characterized based on their particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency (%EE). Additionally, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analyses were performed. Furthermore, advanced characterization techniques such as vibrating sample magnetometry (VSM), Brunauer–Emmett–Teller (BET) method, thermal gravimetric analysis (TGA) and inductively coupled plasma-optical emission spectroscopy (ICP-OES) were employed. In addition to these, in vitro release, hemolytic assay, lactate dehydrogenase (LDH) assay, cell viability and magnetic hyperthermia (MH) analyses of PF127/CA/LEN@pMNCs were performed. Cytotoxicity assay of PF127/CA/LEN@pMNCs under magnetic hyperthermia (MH) exposure conditions was also performed using H22 and Hep3B cells. The successful production of PF127/CA/LEN@pMNCs was confirmed by FTIR spectroscopy and TGA analysis. The optimized PF127/CA/LEN@pMNCs demonstrated 160 nm particle size, −22.80 mV zeta potential, 98% EE, 8.9% loading capacity, hemocompatibility, superparamagnetism, and a prolonged retention time. The iron content of nanoclusters was found to be between 55.78% and 83.91%. Moreover, PF127/CA/LEN@pMNCs exhibited pH responsiveness, and they significantly (p < 0.05) reduced the cell viability of H22 and Hep3B cells. The specific absorption rate of PF127/CA/LEN@pMNCs was 10.79 W g⁻¹ at 10 mg mL⁻¹, indicating their potential for MH. Additionally, significantly (p < 0.05) improved cytotoxicity of PF127/CA/LEN@pMNCs was confirmed against H22 and Hep3B cells under the influence of MH. Collectively, this novel research offers valuable insights into harnessing the diverse potentials of combining existing pharmaceuticals with metallic nanomedicine to effectively treat the intractable liver cancer.