Track: Formulation and Delivery - Chemical - Drug Delivery - Nanoparticles
Category: Poster Abstract
Co-delivery of Paclitaxel and Ritonavir Nanomicelles Targeted with Hyaluronic Acid for Treatment of Metastatic Breast Cancer
Purpose: The primary purpose of this project was the development of self-assembling nanomicelles as a potential treatment for breast cancer. Here we employed polymeric nanomicelles with targeting agent hyaluronic acid (HA) covalently attached on the corona of the nanomicelles. HA binds to CD44 receptors highly expressed on cancer cells as compared to healthy cells. Here we developed HA-targeted polymeric nanomicelles encapsulated a mixture of two drugs; paclitaxel (Ptx) and ritonavir (Rit). Rit is a P-gp inhibitor can reduce the efflux of chemotherapeutic agents. Thus this project was aimed at formulation and development of HA targeted nanomicelles encapsulating PTX+Rit for breast cancer. Methods: HA targeted polymeric naomicelles encapsulating PTX+Rit were prepared with PEG-PLA-HA and Vitamin E TPGS polymers. The hydrodynamic size, zeta potential and the poly dispersity index was determined by a zetasizer particle size analyzer. Entrapment efficiency and the loading efficiency of PTX+Rit was determined simultaneously by an LC-MS/MS method. The cell cytotoxicity of the formulation and its bioactivity was verified using breast cancer cell line; MCF-7A, triple negative breast cancer cell line; MDA-MB-231 and normal breast cell line MCF-12A. Results: An aqueous PTX+Rit nanomicellar formulation targeted with HA was prepared and optimized using Full Factorial design of experiment. HA conjugation to PLA-PEG was confirmed by H1NMR. PTX+Rit nanomicellar formulation had a mean diameter of 117.22 nm, a polydispersity index of 0.19 and a zeta potential of -17.22 mV. Entrapment and loading efficiencies of the formulation were 97.74% and 0.79% for PTX and 95.13 % and 0.72 for Rit respectively. In-vitro cytotoxicity studies such as MTT assay and LDH assay revealed reduction in the IC50 value for a combination of PTX+Rit nanomicelles as compared to PTX nanomicelles. Cellular uptake studies using flow cytometry and intracellular distribution studies using confocal microscopy indicated an increase in uptake of HA targeted PTX+Rit nanomicelles as compared to non-targeted PTX+Rit nanomicelles. Also, HA targeted PTX+Rit nanomicelles were able to reduce the mitochondrial membrane potential in breast cancer cells which resulted in cell apoptosis. Conclusion: An aqueous PTX+Rit nanomicellar formulation was formulated and evaluated for its effectiveness. The potential of targeted nanomicelles to selectively target metastatic breast cancer cells by HA coupled with co-delivery of Paclitaxal with P-gp inhibitor Ritonavir can have a strong anti-cancer effect and possible reversal of multi drug resistance in metastatic breast cancer.
References: Du X, Yin S, Zhou F, et al. Reduction-sensitive mixed micelles for selective intracellular drug delivery to tumor cells and reversal of multidrug resistance. Int J Pharm. 2018;550(1-2):1‐13. doi:10.1016/j.ijpharm.2018.08.019