pH-responsive and targeted delivery of curcumin via phenylboronic acid-functionalized ZnO nanoparticles for breast cancer therapy

Abstract

Abstract
In the recent years, nanoparticle-based targeted delivery of natural bioactive molecules has been achieving much attention for breast cancer treatment. Here, for the first time 3-carboxy phenyl boronic acid (PBA)-tagged and pH-dependent ZnO nanoparticles were fabricated for the cancer cell-specific delivery of curcumin. Curcumin has many limitations (poor solubility, low bioavailability, side effects in other vital body organs etc.) which obstruct its use as a chemotherapeutic molecule. So, curcumin was delivered in cancer cells through nanoparticles to overcome these limitations. Here, ZnO nanoparticle was used as a delivery system as it has many positive sides like good biocompatibility, low cost synthesis process, pH-responsive controlled-released behavior and also Zn2+ ion has toxic effect in cancer cells. It exhibits cytotoxicity through mitochondrial dysfunction, increasing reactive oxygen species (ROS) level, lipid peroxidation, DNA damage and finally apoptosis. Due to PBA tagging with ZnO nanoparticles, the absorption of curcumin is increased in tumor tissue through the interaction with sialic acid (which is overexpressed in the cancer cells). So, we have fabricated ZnO-PBA-Curcumin and have evaluated comparative antitumor efficacy study of the nanoconjugate with free curcumin and free ZnO nanopartices in both in vitro and in vivo system. We have focused mainly on the targeted delivery in cancer cells to reduce the systemic toxicity in the other vital body organs and also have focused in controlled release of the drug molecule in cancer cells to increase the efficiency of the nanoconjugate. ZnO NPs dissolute rapidly to Zn2+ ions at pH lower than 5.5 similar to the acidic tumor microenvironment. Our aim was to increase the anticancer efficacy of curcumin and ZnO in a targeted way avoiding systemic toxicity as possible as that. First, we have verified the successful synthesis of the nanoconjugate using several characterization techniques like (TEM, SEM, EDX, XRD, UV-VIS and Fluorescence spectroscopy, DLS and Zeta potential measurement techniques). All the obtained results confirmed the successful fabrication of ZnO-PBA-Curcumin. We have also examined pH-dependent release nature of curcumin from the nanohybrid in three different buffer solutions (pH 5, 6 and 7.4) in a time dependent manner. Then we have evaluated anticancer efficacy of Zno, free curcumin and ZnO-PBA-Curcumin in vitro model by taking MCF-7 cells (cancerous cell). For that we have performed comparative cytotoxicity study with different doses, intracellular ROS measurement, mitochondrial membrane potential (MMP) measurement, and intracellular uptake study etc. After that, we have also inspected comparative anticancer effect study in vivo solid tumor model
and we have taken swiss albino mice in this purpose. Here, ZnO-PBA-Curcumin exposour was noticed to be more effectual in presenting significant antitumor efficacy compared to equivalent amounts of ZnO NPs and free curcumin. ZnO NPs not only made curcumin more stable but also focused it selectively into tumor tissues, thereby synergistically enhancing its antitumor efficacy. Several biochemical and histological analysis were performed to get such conclusion.
Overall, this study offers an improved, targeted tumor therapy strategy for breast cancer treatment without systemic toxicity, which might also be used in an advanced way in the future.