To overcome the shortcomings of traditional drug delivery strategies using passive targeting in treating localized diseases, researchers have developed various active targeting approaches using stimuli-responsive drug delivery techniques in the past decades. According to a review article in Nature Materials from 2013 by Mura et al., several of these drug delivery technologies appear to suffer from severe downsides hindering their clinical translation, such as absence of degradability, insufficient biocompatibility, inadequate sensitivity to the used trigger for drug release, problems in scaling up and/or complexity of their architectural design. As a result, the author summarizes that only few systems have been tested in pre-clinical models and very few have reached clinical trials, with thermosensitive liposomes (TSL) mentioned as a positive exception and a potential promising candidate.
TSL and Thermosomes
Heat-mediated, clinician-controlled drug delivery through TSL nanoparticles as delivery vehicle
TSLs are exploiting the intravascular drug release by combining heat-triggerable nanocarriers with focused heating of the diseased tissue (such as a tumor). The unique advantage of combining these technologies is that drug deposition in the diseased tissue could be externally controlled spatially and temporally by steering the heating focus and power through the clinician. Applicators for regional or localized heating of even deep-seated tumor tissue to temperatures of up to 42°C are established in clinical practice.
TSLs are designed to release their payload readily and fast when the temperature is increased a few degrees over physiological temperature. This is achieved by a unique biophysical property of the TSL shell, which is composed of selected phospholipids. At body temperature, the shell is hardly permeable due to its tight phospholipid packing. Above a defined threshold temperature, which is adjustable by the phospholipid composition, the shell becomes porous and releases the encapsulated drug in high concentrations.
Several TSL formulations have been developed in the past, with the lysolipid-containing low temperature-sensitive liposome (LTSL) formulation being the most prominent TSL formulations currently being evaluated in clinical studies. An overview of different TSL formulations can be found in review papers summarized here. From a scientific point of view, TSLs have to fulfill two major prerequisites to work clinically in humans:
- Long-term blood circulation half-life at normal temperatures, i.e., stable encapsulation at 37°C to increase the chances that these nanocarriers once circulate through the heated target tissue
- Rapid drug release from the TSLs at elevated temperature, i.e. fast and reliable delivery of the encapsulated drug in the heated target tissue
Most currently known TSL formulations are composed of standard phospholipids such as phosphatidylcholines and PEGylated phospholipids. In addition, they might incorporate surfactants into the membrane to achieve the needed rapid drug release from the nanocarrier. However, surfactants decrease the vesicle stability and thereby negatively impact the blood circulation half-life of these nanocarriers, i.e., the pharmacokinetic without heat activation. This could severely decrease the amount of TSLs that circulate long-enough to get a chance to get activated in the heated target tissue while simultaneously a larger proportion of the drug may leak from these nanocarriers in the first minutes after infusion. As a result, this may rather resemble a sustained release than a targeted, localized drug delivery.
Thermosomes are completely different as they do not incorporate any surfactants into the membrane. Instead, Thermosomes contain a novel, proprietary and patent-protected phospholipid of the family of 1,2-dipalmitoyl-sn-glycero-3-phospho-oligo-glycerol (DPPGn), which are mixed with two commercially available standard phospholipids. This novel class of phospholipids enables both the long-term blood circulation half-life at normal temperatures and rapid release from our Thermosomes at elevated temperatures. As a result, we believe that our proprietary Thermosomes (DPPGn-TSLs) are probably currently the only TSL formulation that fulfills the necessary criteria for heat-triggered drug delivery leveraging the intravascular drug release as they:
- are stable in presence of blood
- show long-circulating properties combined with high plasma levels during the duration of a typical clinical hyperthermia treatment
- have a fast heat-triggered drug release after reaching the heated target tissue