Tocopheryl pullulan-based self assembling nanomicelles for anti-cancer drug delivery

Amphiphilic alpha-tocopherol pullulan polymers (PUTC1, PUTC2, and PUTC3) with different degrees of substitution were synthesized as new carriers for anticancer drugs. The polymers easily self-assembled into nanomicelles through dialysis method. The critical micelle concentrations (CMCs) were 38.0, 8.0, and 4.3 mg/L for PUTC1, PUTC2, and PUTC3, respectively. 10-Hydroxycamptothecin (HCPT) used as a model drug was successfully loaded into the PUTC nanomicelles. Transmission electron microscopy images demonstrated that HCPT-loaded PUTC nanomicelles were almost spherical and had sizes ranging within 171.5-257.8 nm that increased with increased HCPT-loading content, as determined by dynamic laser scattering. The highest encapsulation efficiency of HCPT in PUTC nanomicelles reached 98.3%. The in vitro release of HCPT from PUTC micelles demonstrated sustained release for over 80 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays showed that blank PUTC micelles were nontoxic to normal cells and that the HCPT-loaded PUTC2 nanomicelles showed higher cytotoxicity than the free drug, which was attributed to the enhanced cellular uptake of drug-loaded nanomicelles. Biodistribution experiments showed that PUTC micelles provided an excellent approach to rapid drug transport into cell nuclei. Moreover, the cellular uptake of micelles was found to be an energy-dependent and actin polymerization-associated endocytic process by endocytosis inhibition experiments. These results suggested that PUTC nanomicelles had considerable potential as a drug carrier for drug intracellular delivery in cancer therapy. (C) 2014 Elsevier B.V. All rights reserved.