Protein-based nanocarriers for the oral delivery of paclitaxel

Resumen

Cancer is the second leading cause of death in developed countries following heart and coronary diseases. This pathology refers to a group of diseases that begins with the uncontrolled growth of abnormal cells, in almost any tissue or organ of the body. Chemotherapy is one of the feasible treatments for cancer. Chemotherapy uses medicines to eradicate cancer cells from the body. One of the agents used in treating cancer is paclitaxel, which is an anticancer drug used in ovarian, breast, lung, head and neck cancer, among others. This chemotherapeutic agent is one of the most used drugs due to its potent effect, although there are two important concerns with paclitaxel: its low aqueous solubility and its low oral bioavailability. These limitations prevent the oral administration of this anticancer drug. The general objective of this project was to design and evaluate new and original nanocarriers based on zein to improve the oral bioavailability and antitumor efficacy of paclitaxel in vivo. Zein was used due to its ability to produce nanocarriers by simple methods. Also, it was selected by its ability to form even nanoparticles or nanocapsules. In a first glance, different empty formulations (with no paclitaxel incorporated) were prepared. The different formulations NP, M-NP, M-NP-P, C-NP and MC-NP were characterised and their ability to diffuse in intestinal mucus was assessed. It was observed that as more hydrophilic was the surface of the resulting nanocarriers, their ability to diffuse in mucus was increased. This finding could indicate that the developed formulations would enhance the bioavailability of paclitaxel. Once the empty formulations were well characterised, the anticancer drug paclitaxel (PTX), was incorporated in all the previous formulations. Again, the physico-chemical of all the formulation was evaluated. It was observed that the incorporation of paclitaxel in PTX-NP, PTX-M-NP, PTX-M-NP-P, PTX-C-NP and PTX-MC-NP did not alter the characteristics of the resulting nanocarriers. The release of paclitaxel from the nanocarriers was evaluated and it was observed that the different components of the formulations affected the release rate of the drug. The efficacy of these loaded formulations, previous to its study in superior animals, was evaluated in an in vitro model of Caenorhabditis elegans (C. elegans). This nematode model was chosen due to its reproducibility, its simplicity. Also, this model permits the obtention of results in a short period of time, with an elevated number of worms per study. It was observed that the prepared formulations had different effects in reducing the number of seam cells, which could be correlated with a reduction in the number of cancer cells. Afterwards, a pharmacokinetic study was carried out in mice. All the formulations were tested, and the most important pharmacokinetic parameters were determined. The results obtained in this study matched with those obtained in the nematode study. There were three formulations (PTX-NP, PTX-MC-NP and PTX-C-NP) that were able to increase the oral bioavailability of paclitaxel around 4, 5 and 7 times (respectively), if compared with the commercialised formulation of paclitaxel when administered orally. Two of the best formulations (PTX-C-NP and PTX-MC-NP) were chosen to study its efficacy in an in vivo model of cancer. In this experiment, were the formulations developed in this project were compared with Taxol®, the ability of the formulations to reduce the tumor volume was assessed. It was observed that the oral formulations were as effective as the intravenous Taxol® in reducing the final tumor volume. Furthermore, it was observed that the oral formulations were significantly more efficient in inhibiting the tumor growth than Taxol®. it was also observed that no toxicological effect was on the mice when the formulations were administered orally.