Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery

He Lian¹, Jin Sun¹, Yan Ping Yu¹, Yan Hua Liu², Wen Cao¹, Yong Jun Wang¹, Ying Hua Sun¹, Si Ling Wang¹, Zhong Gui He^1
1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, ²Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Ningxia, People's Republic of China

Background: Nowadays, many cytotoxic anticancer drugs exhibit low solubility and poor tumor selectivity, which means that the drug formulation is very important. For example, in the case of paclitaxel (PTX), Cremophor EL^® (BASF, Ludwigshafen, Germany) needs to be used as a solubilizer in its clinical formulation (Taxol^®, Bristol-Myers Squibb, New York, NY), although it can cause serious side effects. Nanomicellar systems are promising carriers to resolve the above problems, and the polymer chosen is the key element.
Methods: In this study, a novel amphiphilic chitosan/vitamin E succinate (CS-VES) copolymer was successfully synthesized for self-assembling polymeric micelles. Proton nuclear magnetic resonance spectroscopy and infrared were used to characterize the molecular structure of the copolymer. The PTX-loaded CS-VES polymeric micelles (PTX-micelles) were characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry.
Results: The critical micelle concentration of CS-VES was about 12.6 µg/mL, with the degree of amino group substitution being 20.4%. PTX-micelles were prepared by a nanoprecipitation/dispersion technique without any surfactant being involved. PTX-micelles exhibited a drug loading as high as 21.37% and an encapsulation efficiency of 81.12%, with a particle size ranging from 326.3 to 380.8 nm and a zeta potential of +20 mV. In vitro release study showed a near zero-order sustained release, with 51.06%, 50.88%, and 44.35% of the PTX in the micelles being released up to 168 hours at three drug loadings of 7.52%, 14.09%, and 21.37%, respectively. The cellular uptake experiments, conducted by confocal laser scanning microscopy, showed an enhanced cellular uptake efficiency of the CS-VES micelles in MCF-7 cells compared with Taxol. The PTX-micelles exhibited a comparable but delayed cytotoxic effect compared with Taxol against MCF-7 cells, due to the sustained-release characteristics of the nanomicelles. More interestingly, blank nanomicelles based on CS-VES copolymer demonstrated significant cytotoxicity against MCF-7 cells.
Conclusion: The supramolecular micellar aggregates based on CS-VES copolymer is a promising nanocarrier and efficacy enhancer when used as an anticancer drug-delivery system.

Keywords: nanomicelles, cellular uptake, cytotoxicity