Precise control of drug release from nanoparticles can improve efficacy and reduce systemic toxicity associated with administration of certain medications. Here, we combined two phenomena, photothermal conversion in plasmon resonant gold coating and thermal sensitivity of liposome compositions, to achieve a drug delivery system that rapidly releases doxorubicin in response to external stimulus.Methods: Thermosensitive liposomes were loaded with doxorubicin and gold-coated to produce plasmon resonant drug delivery system. Plasmon resonance facilitates release of contents upon near-infrared laser illumination, thus providing spatial and temporal control of the process. This controlled delivery system was compared to thermosensitive liposomes without gold coating and to the FDA-approved Doxil that was gold-coated to create a plasmon resonant coating. Release of doxorubicin from the gold-coated thermosensitive liposomes was further confirmed by tests of cell viability.Results: Upon laser illumination at 760 nm and 88 mW/cm2 power density, permeability of plasmon resonant liposomes increased by three orders of magnitude, from 70×10-12 to 60,000x10-12 cm/s. In control experiments, mild hyperthermia (42°C) increased permeability of these thermosensitive liposomes to just 3,700×10-12 cm/s. Neither hyperthermia nor laser illumination elicit content release from Doxil or plasmon resonant Doxil obtained by gold coating. Laser-induced release of doxorubicin from plasmon resonant thermosensitive liposomes resulted in the loss of cell viability significantly greater than in any of the control groups.Conclusion: Combination of thermosensitive liposomes with plasmon resonant coating enables rapid, controlled release, not currently available in pharmaceutical formulations of anticancer drugs.

Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil ® and Ambisome ® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37 o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5 o C increase in temperature or by laser illumination (760 nm and 88 mW/cm 2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.