Thermosensitive liposomal drug delivery systems: state of the art review

Abstract

Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine.

Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields

“…There have been many attempts to use chemical cues to trigger the target-specific release, such as acidic pH in the tumors, low endosomal/lysosomal pH, reductive intracellular environments, and tumor specific-enzymes (cathepsins, metalloproteases, etc.) [14–16]. However, one should admit that the fidelity and robustness of these strategies might not be sufficient to achieve the desired goals.…”

Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

“…Since hyperthermia also can increase cellular membrane fluidity, drug diffusion through the cell membrane can be increased. Early hyperthermia studies with passively targeted conventional and stealth liposomes revealed heating allowed more liposome extravasation, however the temperatures used were not sufficient for drug release within the tumor [25, 26]. These findings led to the design of thermosensitive liposomes which have been formulated to release their contents upon heating by incorporating lipids with phase transition properties in the heating temperature range, lysolipids or thermosensitive polymers [21, 23].…”

“…Another problem has been low intratumoral penetration of the drug released from the liposome because of redistribution in the circulation following intravascular release [3, 71–73]. Currently, several strategies are being investigated to improve liposome-based hyperthermia [25, 26]. These approaches include utilizing newer pegylated thermosensitive liposome and leucine zipper peptide-lipid hybrid formulations with improved in vivo drug retention and increased doxorubicin bioavailability in tumors [71, 73].…”

“…By applying an external stimulus to the local tumor region, the liposomes located within the tumor are triggered to release their drug payload. The free drug can readily diffuse (depending on the tissue binding affinity of free drug) and be taken up by tumor cells [2, 7, 25]. A limiting factor with this strategy is there must be sufficient drug levels available to kill all tumor cells.…”

Metal Complexes as MRI Contrast Enhancement Agents

“…212 Temperature-sensitive liposomes have been also studied in vivo in guided hyperthermia treatment of cancer. 213,214 Liposomes containing a paramagnetic Mn 2+ salt or a Gd 3+ complex and doxorubicin have been tested to detect drug release. 215 …”