Biodegradable and biocompatible nanoparticles for controlled release of paclitaxel and fluorouracil for the treatment of Hepatocellular Carcinoma (HCC)

Abstract

Cancer represents one of the greatest threats to human health and Hepatocellular Carcinoma (HCC) is one of the most incident Cancers and the third main reason of Cancer death worldwide. Thus, the development of new and more effective therapies against HCC has attracted increased attention in the medical and pharmaceutical fields, since traditional chemotherapy treatments do not have a high efficacy in prolonging the survival of HCC patients, mainly due to the resistance acquired to medicines. This doctoral project therefore proposes to evaluate the use of an amphiphilic copolymer based on pullulan (PUL) grafted with poly(lysine) (PLL) for the development of biodegradable nanoparticles capable of encapsulating and releasing, in a controlled and localized way, two chemotherapeutic agents, paclitaxel (PTX) and fluorouracil (5-FU). In addition, 2-chloro-N,N-diethylethylamine hydrochloride (DEAE) molecules will be grafted onto pullulan chains, in order to obtain pH-sensitive nanoparticles capable of triggering the release of the active substances at the more acidic pH of the tumor. The copolymers will be characterized by usual techniques such as Hydrogen and Carbon Nuclear Magnetic Resonance (1H NMR and 13C NMR), Gel Permeation Chromatography (GPC), among others. The nanoparticles will be synthesized via dialysis and characterized by Dynamic Light Scattering (DLS), X-ray diffractometry (XRD), Transmission and Scanning Electron Microscopy (TEM and SEM), Atomic Force Microscopy (AFM), among others. The materials synthesized in the present proposal will have their toxicity assessed by in vitro cytotoxic assays. The kinetics of in vitro release of the active principles will be carefully evaluated in fluids that simulate the physiological environment, varying the pH of the medium. (AU)