Synthesis, Characterization,In Vitro and In Vivo Toxicity, and Antitumor Efficacy Potential of a Targeted Drug Delivery System Based on Hyaluronic Acid-Functionalized Cisplatin-Loaded Mesoporous Silica Nanoparticle (MSN) in the Treatment of Non-Small Cell Lung Cancer
Project no. 28473 · Status: Kapanmış · 2023
Summary
<p>Lung cancer is the most common cancer and also the most lethal. When examined histologically, it is divided into two types as small cell and non-small cell lung cancer, and non-small cell lung cancer (NSCLC) cases constitute 85% of the disease. Cisplatin (CDDP) is a chemotherapeutic agent widely used in the treatment of non-small cell lung cancer. On the other hand, in addition to this widespread use, CDDP causes a series of serious side effects such as nausea, vomiting, nephrotoxicity, cardiotoxicity, hepatotoxicity and neurotoxicity. In order to overcome these problems, nanotechnology-based smart drug studies have been carried out with an increasing tendency, especially in recent years. Mesoporous silica nanoparticles (MSN) are frequently preferred as drug carriers in drug targeting studies due to their biocompatible and biodegradable structure as well as their high drug loading capacity. In addition, the ease of surface modification provides a great advantage in terms of targeting. A549-Luc-C8 lung cancer cells overexpress the CD44 receptor, which plays a role in tumor development, metastasis, drug resistance and disease diagnosis, compared to healthy cells. Drug targeting studies are commonly carried out by modifying nanoparticles with Hyaluronic acid (HA), which specifically binds to this receptor, CD44. In this project, after the synthesis of MSN, the nanoparticle surface was functionalized using high molecular weight HA (HMWHA) and loaded with CDDP. Thus, a targeted nanoparticle HA-MSN-CDDP was produced for the treatment of non-small cell lung cancer. The antitumor efficacy and side-effect reduction potential of this CD44-targeted drug delivery system were investigated in vitro and in vivo using a xenograft lung cancer model. The nanoparticles synthesized within the scope of the project were characterized by FTIR, DLS, SEM, TEM, and BET analyses. HA-MSN-CDDP has a size of 50-60 nm, a negative surface charge, a regular mesoporous structure, a spherical morphology, and a high drug delivery capacity. It was confirmed that HA-MSN-CDDP was taken up by CD44-positive A549-Luc-C8 cells via endocytosis. The anticancer drug delivery system targeting CD44 with HA showed effective cytotoxic activity on A549-Luc-C8 lung cancer cells and led to the death of these cells by inducing apoptosis at a high rate. In addition, the non-specific cytotoxic activity caused by CDDP on healthy CCD-34Lu lung cells was reduced thanks to this targeted drug delivery system. It has been shown that these nanoparticles can be safely used in intravenous applications. Furthermore, it was demonstrated by the AMES test that they reduced the mutagenic activity caused by CDDP. A xenograft model of non-small cell lung cancer was developed by subcutaneously administering A549-Luc-C8 cells to Balb/c nude mice, and the tumor sizes were monitored using IVIS. HA-MSN-CDDP effectively reduced tumor size thanks to its specific targeting of CD44. This developed targeted anticancer drug delivery system ensured the preservation of antioxidant enzyme levels. Furthermore, histological analyses revealed that the nephrotoxic effects of CDDP were reduced via the targeted nanoparticle HA-MSN-CDDP. Based on these results, HA-MSN-CDDP has significant potential for the treatment of NSCLC. Its high biocompatibility, controlled drug release, and effective tumor suppression properties make HA-MSN-CDDP a valuable candidate for preclinical and clinical development.</p>