CKAAKN peptide-conjugated long-circulating nanoliposomes for the targeted delivery of oridonin to pancreatic cancers.

Pancreatic cancer has a dismal prognosis due to the rapid progression and inefficiency of chemotherapy. To ameliorate this inefficiency of chemotherapy drug, we developed a long-circulating PEGylated nanoliposome (ORI@PD-Lipo) with 1,2-distearoylphosphoethanolamine- polyethyleneglycol-amine (DSPE-PEG-NH) to deliver oridonin, one of the active ingredients in Rabdosia rubescens (R. rubescens) in this study. For improving tumor-targeting delivery of oridonin, a pancreatic cancer targeting CKAAKN peptide was used to modify the nanoliposome (ORI@CPD-Lipo). Our results showed that ORI@CPD-Lipo had good stability and biosafety with average particle size of about 100 nm, which could selectively internalize into pancreatic cancer cells BxPC-3 during the short incubation time (1-4 h) in vitro under the mediation of CKAAKN peptide, compared with HPDE6-C7 cells. Furtherly, significantly higher uptake of ORI@CPD-Lipo nanoparticles by BxPC-3 tumors (positive-CKAAKN) than normal pancreatic tissue was observed in vivo during the whole experiment process (1-48 h), with increased ratio on experiment time. Our data also indicated the treatment of BxPC-3 cells with ORI@CPD-Lipo nanoparticles showed significantly enhanced antitumor effect and therapeutic efficacy than the treatment with the free ORI, non-targeting ORI@Lipo and CKAAKN-blocking ORI@CPD-Lipo. The enhanced antitumor activity to BxPC-3 cells should be attributed to the enhanced drug cellular uptake mediated by ORI@CPD-Lipo nanoparticles, chemical toxicity of the released ORI from the nanoparticles. Our study provided a valuable reference and strategy of CKAAKN-mediated targeting cancer chemotherapy based on ORI@CPD-Lipo against the pancreatic tumor.