Formulation optimization and in vivo proof-of-concept study of thermosensitive liposomes balanced by phospholipid, elastin-like polypeptide, and cholesterol

PLoS One. 2014 Jul 28;9(7):e103116. doi: 10.1371/journal.pone.0103116. eCollection 2014.

Abstract

One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Chemistry, Pharmaceutical
  • Cholesterol / chemistry*
  • Disease Models, Animal
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacokinetics
  • Drug Delivery Systems
  • Drug Liberation
  • Humans
  • Lipid Bilayers / chemistry
  • Liposomes / chemistry*
  • Male
  • Mice
  • Molecular Docking Simulation
  • Nanoparticles / chemistry
  • Nanoparticles / ultrastructure
  • Particle Size
  • Peptides / chemistry*
  • Phospholipids / chemistry*
  • Thermodynamics
  • Transition Temperature
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • Lipid Bilayers
  • Liposomes
  • Peptides
  • Phospholipids
  • Doxorubicin
  • Cholesterol

Grants and funding

The simulation part of this research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (2012R1A1A1001196), and by the National Institute of Supercomputing and Networking/Korea Institute of Science and Technology Information with supercomputing resources, including technical support (KSC-2013-C2-18). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.