Nanomicelles based on X-shaped four-armed peglyated distearylglycerol as long circulating system for doxorubicin delivery.

Abstract A novel X-shaped four-armed gemini-like peglyated distearylglycerol (Gemini-PEG 2K -GCDS), with two hydrophilic PEG heads and two hydrophobic stearic acid tails, was successfully synthesized and used as a nanomicellar carrier for delivery of doxorubicin. The critical micelle concentration of the amphiphilic copolymer was higher than 10 −6 . Mean particle size and zeta potential of DOX-encapsulated Gemini-PEG 2K -GCDS nanomicelles (DOX-GNMs) was 20.4 nm and +3.91 mv, respectively. Encapsulation efficiency of DOX-GNMs was as high as 94.6 and DOX release was pH-dependent from DOX-GNMs, ensuring the stability of nanomicelles in blood circulation and rapid release of DOX in tumor cells. Pharmacokinetic studies in rats following i.v. administration, DOX-GNMs demonstrated longer retention in blood and larger AUC (19.1-fold of t 1/2 and 12.9-fold of AUC) compared with DOX solutions (DOX-Sol). Tissue distribution studies indicate that DOX-GNMs had higher tumor accumulation (4.6-fold) and lower heart toxicity in H22 tumor-bearing mice (17.4-fold) at 48 h after administration in comparison with DOX-Sol. Moreover, IC 50 of DOX-GNMs increased by 3.3-fold, 2.0-fold and 2.3-fold compared with DOX-Sol in P-gp over-expressing MCF-7/Adr cells after 24 h, 48 h and 72 h, internalized via macropinocytosis-mediated and clathrin-mediated endocytosis. This study suggests that Gemini-PEG 2K -GCDS nanomicelle is a promising long circulating delivery system for anti-tumor drugs via extended blood circulation and improved tumor distribution.