Development of phenylboronic acid functionalized poly (lactic-<i>co</i>-glycolic acid) nanoparticles for novel co-delivery of chemo-herbal combination towards lung cancer: an <i>in silico</i> and <i>in vitro</i> proof of concept

This study includes a novel chemo-herbal combination using biochanin A (BCA) and lenvatinib (LTB) to synergize each other's anti-cancer activities. Phenylboronic acid (PBA)-functionalized poly (lactic-<i>co</i>-glycolic acid) (PLGA) was employed to specifically target the sialic acid overexpressed in lung cancer. ATR, DSC, and NMR studies confirmed the successful synthesis of PBA-PLGA, which was further utilized for the development of BCA and LTB co-loaded PBA-PLGA nanoparticles (PBA-PLGA-BCA-LTB NPs). A higher <i>in silico</i> docking score between LTB and different proteins of endothelial growth factor receptors (EGFRs) and a combination index value <1 supported the chemo-herbal combination regimen for lung cancer. In addition, the significantly higher protein expression (cle-PARP and cle-cas-3) from BCA-LTB explains the strong apoptotic effect. The optimized PBA-PLGA-BCA-LTB NPs exhibited a 182.2 ± 6.88 nm, 0.134 ± 0.074 polydispersity index, and -32.2 ± 3.40 mV zeta potential. ATR, DSC, and PXRD studies confirmed the amorphous dispersion of BCA-LTB in the PBA-PLGA matrix. A higher binding constant and rate coefficient, with a Δ<i>H</i> of -5.69 ± 0.183 (kcal mol^-1), Δ<i>G</i> of -4.98 (kcal mol^-1), and -<i>T</i>Δ<i>S</i> of 0.706 (kcal mol^-1) using isothermal titration calorimetry (ITC) explained the enthalpy-driven specificity of PBA-PLGA towards sialic acid (Neu5AC). The prepared NPs showed physical stability at 4 ± 2 °C and were non-hemolytic and stable with plasma proteins. Significantly higher cytotoxicity and cellular uptake were observed for PBA-PLGA-BCA-LTB NPs in contrast to PLGA-BCA-LTB NPs and coarse-BCA-LTB. The PBA-PLGA-BCA-LTB NPs also exhibited anti-migration and invasion potential for A549 cells. <i>In vivo</i> pharmacokinetic studies indicated an increase in plasma half-life of the drugs and a decrease in hematological toxicities using PBA-PLGA-BCA-LTB NPs compared to free BCA-LTB. In summary, the PBA-PLGA-BCA-LTB NPs represent a biocompatible, potential, cancer-targeted, and effective treatment option for lung cancer treatment.