In vitro evaluation of intestinal permeability of mucoadhesive polymeric nanoparticles containing methotrexate in a triple co-culture cells model

Abstract

Colorectal cancer is the third highest worldwide incidence, with more than 1.4 million diagnoses in 2015 and about 690,000 deaths, emphasizing the urgent need for research for new therapeutic alternatives for the treatment of this pathology. In this context, the pharmaceutical nanotechnology is a relevant technological tool for the development of new systems for the target of chemotherapeutic drugs. Due to their small size, nanoparticles are able to move by capillaries that supplying the tumour tissue, escaping of phagocytosis by immune cells and passively permeate cells and tissues. Further, these systems enable the encapsulation of low-stability drugs, protecting them against premature degradation and / or allowing the modulation of their release rate. Methotrexate (MTX) is one of the most widely used drugs in the treatment of solid tumours drugs, however, by it highly cytotoxic and non-selective action, this drug promotes many side effects. Allied to this, its therapeutic efficiency is compromised due to acquired resistance by tumour cells, mainly through the efflux mechanism of MTX free form. In this context, the design of innovative systems allowing the target of chemotherapeutics to the tumour tissue and further improve the interaction with the tumour biointerface, is a rational strategy to maximize therapeutic efficacy of these drugs. Thus, the placement of MTX into a nanostructured system composed of polymers with properties such as pH dependent solubility and mucoadhesive capacity, which can also favour the target and cellular internalization, is a promising approach to achieving the target ad release of MTX to the colon from an oral administration. In this master's project developed by the student Fernanda Isadora Boni student, chitosan (QS) nanoparticles, hyaluronic acid (HA) and hydroxypropylmethylcellulose phthalate (HPMCP) has been explored, since these polymers aggregate the desirable properties of mucoadhesiviness, potential interaction with overexpressed receptors on the surface of tumour cells and pH dependent behaviour. The nanoparticles were obtained by polyelectrolytic complexation process, characterized and are under the studies on the drug release profile. This project aims the in vitro study of intestinal permeability of nanoparticle composed by QS, AH and HPMCP containing MTX using triple co-culture cellular model, which mimic the human intestinal epithelium in the presence of mucus and specialized cells, to be held at the Institute of Biomedical Engineering, University of Porto, in Portugal, under the supervision of Prof. Dr. Bruno Sarmento. This study will contribute decisively to the understanding of the influence of mucus in the release and permeation of MTX carried in the proposed system. (AU)