Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles

Background: One of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chitosan (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities. Materials and methods: MTX was incorporated into NPs (112.8-171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4-35.0 mV and MTX loading efficiency of 17.1%-18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4. Results: The in vitro cellular uptake study showed that MTX accumulation in J774A. 1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC(0-72) h (area under the plasma drug concentration-time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC(0-72) h. Conclusion: The biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery.