Thiomer-coated solid lipid nanoparticles for the glutathione and temperature-responsive drug delivery against breast cancer

Abstract

Breast cancer is the most prevalent type of cancer among women. Despite extensive efforts, existing cancer therapies often yield suboptimal outcomes due to their inherent off-target toxicity and the emergence of multidrug resistance in tumor cells. Thus, there exists a pressing need to explore innovative nanotechnology-based drug delivery systems to address these challenges. The present study aimed to develop temperature and glutathione (GSH)-responsive nanocarriers to selectively deliver 5-Fluorouracil (5-FU) to the breast cancer tumor. For this purpose, 5-FU loaded temperature-sensitive solid lipid nanoparticles (SLNs) were formulated using Lauric Acid and Oleic acid-based binary mixture with a melting range of 39–42 °C. A glutathione-responsive polymeric coating of folate grafted thiolated chitosan (FTCS) was coated onto developed lipid cores and evaluated in terms of physicochemical characterization, in-vitro drug release in normal physiological conditions as well as in the presence of glutathione and at a temperature of 39 °C. Evaluation of anticancer activities was carried out in vitro using MDA-MB-123 cancer cell lines and in-vivo in a chemical-induced breast cancer rat model. FTCS-SLN-5-FU exhibited an average size of 274.6 ± 2.62 nm and zeta potential of +18.74 ± 0.22 mV as compared to non-coated 5-FU loaded nanoformulation (SLN-5-FU) with average particle size of 184 ± 20.51 nm and zeta potential of 19 ± 0.27 mV, thus confirming the successful coating of the cationic FTCS. The SEM images of formulations showed well-defined nano-sized particles. In-vitro drug release studies have confirmed the glutathione and temperature-sensitive behavior of FTCS-SLN-5-FU, indicating 80.32 ± 8.5 % of 5-FU release at pH 5.8, 39 °C temperature in the presence of 20 mM glutathione compared to 10.21 % ± 1.89 % of drug release at pH 7.4 during the first 24 h. Invitro anticancer activity revealed a significantly reduced viability in the case of FTCS-SLN-5-FU compared to SLN-5-FU. Similarly, In-vivo anticancer activity in breast cancer-induced rat models indicated significantly reduced tumor weight compared to SLN-5-FU and 5-FU. The results provided proof of the concept that utilizing temperature and GSH-sensitive nanocarriers can be a suitable strategy to enhance the intratumoral delivery and thus anticancer activity of the drugs.