Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging

PLoS One. 2017 Sep 21;12(9):e0185116. doi: 10.1371/journal.pone.0185116. eCollection 2017.

Abstract

In numerous studies, liposomes have been used to deliver anticancer drugs such as doxorubicin to local heat-triggered tumor. Here, we investigate: (i) the ability of thermosensitive liposomal nanoparticle (TSLnp) as a delivery system to deliver poorly membrane-permeable anticancer drug, gemcitabine (Gem) to solid pancreatic tumor with the aid of local mild hyperthermia and, (ii) the possibility of using gadolinium (Magnevist®) loaded-TSLnps (Gd-TSLnps) to increase magnetic resonance imaging (MRI) contrast in solid tumor. In this study, we developed and tested gemcitabine-loaded thermosensitive liposomal nanoparticles (Gem-TSLnps) and gadolinium-loaded thermosensitive liposomal nanoparticles (Gd-TSLnps) both in in-vitro and in-vivo. The TSLnps exhibited temperature-dependent release of Gem, at 40-42°C, 65% of Gem was released within 10 min, whereas < 23% Gem leakage occurred at 37°C after a period of 2 h. The pharmacokinetic parameters and tissue distribution of both Gem-TSLnps and Gd-TSLnps were significantly greater compared with free Gem and Gd, while Gem-TSLnps plasma clearance was reduced by 17-fold and that of Gd-TSLpns was decreased by 2-fold. Area under the plasma concentration time curve (AUC) of Gem-TSLnps (35.17± 0.04 μghr/mL) was significantly higher than that of free Gem (2.09 ± 0.01 μghr/mL) whereas, AUC of Gd-TSLnps was higher than free Gd by 3.9 fold high. TSLnps showed significant Gem accumulation in heated tumor relative to free Gem. Similar trend of increased Gd-TSLnps accumulation was observed in non-heated tumor compared to that of free Gd; however, no significant difference in MRI contrast enhancement between free Gd and Gd-TSLnps ex-vivo tumor images was observed. Despite Gem-TSLnps dose being half of free Gem dose, antitumor efficacy of Gem-TSLnps was comparable to that of free Gem(Gem-TSLnps 10 mg Gem/kg compared with free Gem 20 mg/kg). Overall, the findings suggest that TSLnps may be used to improve Gem delivery and enhance its antitumor activity. However, the formulation of Gd-TSLnp needs to be fully optimized to significantly enhance MRI contrast in tumor.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Area Under Curve
  • Cell Line, Tumor
  • Contrast Media* / pharmacokinetics
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacokinetics
  • Drug Delivery Systems
  • Drug Liberation
  • Female
  • Gadolinium / administration & dosage
  • Gadolinium / pharmacokinetics
  • Gemcitabine
  • Hot Temperature
  • Liposomes*
  • Magnetic Resonance Imaging* / instrumentation
  • Mice, Nude
  • Models, Biological
  • Nanoparticles
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / diagnostic imaging
  • Pancreatic Neoplasms / drug therapy*
  • Particle Size
  • Phantoms, Imaging
  • Viscosity

Substances

  • Antineoplastic Agents
  • Contrast Media
  • Liposomes
  • Deoxycytidine
  • Gadolinium
  • Gemcitabine