Modeling diffusion in theranostic nanocarriers for biomedical application: paclitaxel and PLGA nanoconstructs

Enormous efforts have been made, and still are ongoing, in the field of the research on nanomedicine over the last few decades. Among the many biomedical applications for nanotechnologies, drug delivery systems based on lipid or polymer nanoparticles have shown a promising potential, as alternative to the typical techniques, for the treatment of a wide range of tumoral and respiratory diseases. In this context, South Korea turned out to be one of the most active countries. A research group composed by biologists, chemicals and nanotechnologists, located in the Yonsei University medical research department of Wonju, had been committed on the development and improvement of the therapeutic efficacy and safety of micro-sized polymeric particles as carriers for the transport and delivery of lung-targeted drugs. They mainly focused their attention to synthetize and study PLGA-based discoidal particles and proved the feasibility and great potential of this technology for the targeted treatment of various pulmonary diseases. The innovative work reported in this text has the ambitious purpose to create a simulation model that, in parallel with the experimental sessions performed in the laboratories, reproduced the chemical structure of the drug-loaded polymer matrix of PLGA 50:50 at nanoscale. The modelling software used to realize realistic MD simulations is Gromacs whose main functions are widely discussed. The strict synergy and collaboration between the two authors, as well as with the hosting group of researchers, has allowed to deeply investigate the behavior of drugs in bulk water and within the hydrated polymeric particle in terms of their diffusion. In particular, two different types of drugs were considered, Paclitaxel and Curcumin. My personal concern was to produce a consistent model of diffusion in water for PTX and to validate it by comparing the obtained results to that found with intense researches in literature, while my colleague and coauthor dealt with the case study of Curcumin. The validation of water models for free drugs represented the starting step for a successive investigation of the drug diffusion into a PLGA nanoconstruct. Recurring to some tools suitable to the polymer assembling, I was able to build this polymer in the way of having as similar properties as possible with that used in the experiments. Last part of the work consisted in the design of a geometrical setup for different configurations of Curcumin-loaded PLGA which respected the actual values of PLGA density and hydration level. The technique of the fractional factorial design was applied to perform a sensitivity analysis on the diffusion phenomenon and to ensure to get results having statistical relevance. At last, on the base of the diffusion coefficients obtained through simulations, it was possible to produce the release profiles of the drugs from the polymer surface by mean of a release model created ad hoc. Finally, experimental data were fitted and the release curves compared to the trends resulting from the model. In this way, the goodness and reliability of the developed model has been demonstrated and the deviation existing among numerical solution and experimental values has provided an idea of the contribute of degradation phenomenon acting on the PLGA particles when tested in-vivo.