In vitro and in vivo antitumor activity of gemcitabine loaded thermosensitive liposomal nanoparticles and mild hyperthermia in pancreatic cancer

The study was designed to explore the feasibility of increasing the delivery of gemcitabine-HCL (Gem), a poor membrane permeable and short half-life drug, through PEGylated thermosensitive liposomal nanoparticles (TSLnps) delivery system followed by mild hyperthermia (mTH) at 42oC. In vitro release pattern of Gem-TSLnps showed a significant Gem release (60%, p<0.01) at 42oC compared to that released at 37oC (29%). Cell viability and clonogenic assay demonstrated significant inhibition of MiaPaCa-2 cells growth by Gem-TSLnps + mHT compared to Gem alone. Further, IC50 value of Gem treated cells was (0.077?M) 1.2 fold higher compared to that treated with Gem-TSLnps + mHT (0.063 ?M). mHT treated cells showed moderate inhibition of cell growth compared to controls. For cellular uptake studies, flow cytometric analysis and confocal imaging revealed higher uptake of Rho-TSLnps compared to Rho-PE or untreated cells. Tumor volume of mice treated with Gem alone was 1.8 fold higher compared to the group treated with Gem-TSLnps + mHT. Further, tumor regression of Gem-TSLnps + mHT treated group was significantly higher (p<0.01) compared to Gem-TSLnps or Gem. No significant elevated liver enzymes were observed when serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of control group was compared to that of Gem or Gem-TSLnps+mHT treated groups. However, serum level of alkaline phosphatase (ALP) of Gem or Gem-TSLnps+ mHT treated group was significantly elevated (p<0.05) when compared to the control group. In conclusion, TSLnps increased the delivery of Gem to tumor cells and also enhanced significantly the antitumor activity of Gem when combined with heat.