Molecular simulation and in vitro evaluation of chitosan nanoparticles as drug delivery systems for the controlled release of anticancer drug cytarabine against solid tumours.

The present work is an attempt to integrate the molecular simulation studies with in vitro cytotoxicity of cytarabine-loaded chitosan nanoparticles and exploring the potential of this formulation as therapeutics for treating solid tumours. The molecular simulation was performed using GROMACS v5.4 in which, chitosan polymer (CHT; six molecules) was used to study the encapsulation and release of a single molecule of cytarabine. Root Mean Square Deviation (RMSD) of the Cα atom of cytarabine (CBR) molecule shows that CBR starts to diffuse out of the CHT polymer binding pocket around 10.2 ns, indicated by increased fluctuation of RMSD at pH 6.4, while the drug diffusion is delayed at pH 7.4 and starts diffusing around 17.5 ns. Cytarabine-loaded chitosan nanoparticles (CCNP), prepared by ionic gelation method were characterized for encapsulation efficiency, particle size and morphology, zeta potential, crystallinity and drug release profile at pH 6.4 and 7.4. CCNPs showed 64% encapsulation efficiency with an average diameter of 100 nm and zeta potential of + 53.9 mV. It was found that cytarabine existed in amorphous state in nanoformulation. In vitro release studies showed 70% cytarabine was released from the chitosan-based nanoformulation release at pH 6.4, which coincides with the pH of tumour microenvironment. Cytotoxicity against breast cancer cell line (MCF 7) was higher for nanoformulation compared to free cytarabine. Haemocompatibility studies showed that chitosan-based nanoformulation is safe, biocompatible and nonhaemolytic in nature; hence, can be used as a safe drug delivery system. Taken together, our study suggests that chitosan nanoformulation would be an effective strategy for the pH-dependent release of cytarabine against solid tumours and might impart better therapeutic efficiency.