LAUSR

Simple Summary Various nanoparticles have been developed over the last few decades for targeted drug delivery to cancerous tumors while reducing toxicities. Thermosensitive liposomes (TSL) belong to the category of triggered nanoparticle delivery systems, where drug release occurs in response to hyperthermic temperatures (typically, >40 ºC). After administration, the TSL-encapsulated drug circulates for extended duration (hours) in the blood stream. Localized hyperthermia of the targeted tissue results in localized drug release, enabling up to 25x tumor drug uptake compared to administration of unencapsulated drug. Here, we review the delivery kinetics of TSL and discuss how the interaction between drug, TSL and hyperthermia device affects drug delivery. Thus, this review provides guidelines on how to improve drug delivery by optimizing the combination of TSL, drug, and hyperthermia method. Many of the concepts discussed are applicable to a variety of other triggered nanoparticle delivery systems. Abstract Thermosensitive liposomes (TSL) are triggered nanoparticles that release the encapsulated drug in response to hyperthermia. Combined with localized hyperthermia, TSL enabled loco-regional drug delivery to tumors with reduced systemic toxicities. More recent TSL formulations are based on intravascular triggered release, where drug release occurs within the microvasculature. Thus, this delivery strategy does not require enhanced permeability and retention (EPR). Compared to traditional nanoparticle drug delivery systems based on EPR with passive or active tumor targeting (typically <5%ID/g tumor), TSL can achieve superior tumor drug uptake (>10%ID/g tumor). Numerous TSL formulations have been combined with various drugs and hyperthermia devices in preclinical and clinical studies over the last four decades. Here, we review how the properties of TSL dictate delivery and discuss the advantages of rapid drug release from TSL. We show the benefits of selecting a drug with rapid extraction by tissue, and with quick cellular uptake. Furthermore, the optimal characteristics of hyperthermia devices are reviewed, and impact of tumor biology and cancer cell characteristics are discussed. Thus, this review provides guidelines on how to improve drug delivery with TSL by optimizing the combination of TSL, drug, and hyperthermia method. Many of the concepts discussed are applicable to a variety of other triggered drug delivery systems.