Preparation and Characterization of Lipid-Based Smart Nanostructures and Investigation of Their Potential Usage in Breast Cancer Combined Therapy

Abstract

Triple negative breast cancer (TNBC), which accounts for 15–20% of incident breast cancers, is a highly aggressive cancer type with the worst prognosis among breast cancer subtypes. The development of an effective therapeutic method is significant to improve the survival rate of TNBC cancer patients. Although chemotherapy is a widespread treatment for TNBC, it needs to be improved to increase treatment success. Therefore, applying a different treatment method, such as photothermal therapy (PTT) together with chemotherapy is very significant. PTT has emerged as a noninvasive and reliable cancer-therapy modality, which could rapidly increase the temperature of tumor cells and further ablate the tumors by activating photosensitizer and producing thermal energy under near-infrared (NIR) light irradiation. Magnetic hyperthermia is another complementary approach to cancer treatment. This term is explained by applying an alternating magnetic field (AMF) to a magnetic material, producing a temperature rise. Superparamagnetic iron oxide nanoparticles have attracted attention in the biomedical field for their ability to induce hyperthermia in response to an alternating magnetic field. Although the combined treatment using chemotherapy and photothermal therapy is promising, another problem to be considered is the prevention of multidrug resistance (MDR). MDR describes a phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are chemotherapy agents. The dual use of a chemotherapy agent with a chemosensitizer, which tends to lower MDR, will increase the effectiveness of the chemotherapy agent and will be more effective in the treatment of TNBC. In addition, it is very important to use a drug delivery system to prolong the plasma circulation time of the drug and inorganic nanoparticles and to reduce contact with normal cells. Considering these situations, nanostructured lipid carriers (NLC) have been developed for use in chemotherapy and photothermal therapy within the scope of this study. NLCs originate in an unstructured solid matrix composed of a mixture of both liquid and solid lipids, a surfactant or mixture of surfactants, and an aqueous phase. In this study, stearic acid was used as solid lipid and oleic acid was used as liquid lipid in the synthesis of NLCs and the size and crystallinity changes were investigated by increasing the amount of oleic acid using DLS, AFM, TEM, 1H-NMR and DSC. Then, in-vitro release profiles and kinetic models were investigated by encapsulating ion-paired doxorubicin (DOX-OA) and verapamil hydrochloride (VERA) into NLC. Gold nanoparticles (AuNPs) have been used as hyperthermia agents due to their various properties, such as high surface-volume ratios, easy size and geometry control, and high dispersibility in aqueous media to investigate the potential for use for PTT. AuNPs with spherical, rod and cube geometry were used to examine the effect of gold geometry on photothermal profile and photothermal conversion efficiency. While examining this effect, the most suitable geometry to be used as a PTT agent was investigated by changing parameters such as concentration, NLC particle density, power and time. In the next part of the study, active pharmaceutical ingredients (APIs) and AuNPs were co-encapsulated in NLC and in-vitro release studies were performed by exposure to 808 nm NIR radiation. The cell killing potentials of the developed formulations were evaluated on breast cancer cells (MDA-MB-231 cell line) with and without NIR irradiation. In addition, magnetic nanoparticles were encapsulated in NLC to investigate the potential use for magnetic hyperthermia.