Rapid Light-Triggered Drug Release in Liposomes Containing Small Amounts of Unsaturated and Porphyrin-Phospholipids

Prompt membrane permeabilization is a requisite for liposomes designed for local stimuli‐induced intravascular release of therapeutic payloads. Incorporation of a small amount (i.e., 5 molar percent) of an unsaturated phospholipid, such as dioleoylphosphatidylcholine (DOPC), accelerates near infrared (NIR) light‐triggered doxorubicin release in porphyrin–phospholipid (PoP) liposomes by an order of magnitude. In physiological conditions in vitro, the loaded drug can be released in a minute under NIR irradiation, while liposomes maintain serum stability otherwise. This enables rapid laser‐induced drug release using remarkably low amounts of PoP (i.e., 0.3 molar percent). Light‐triggered drug release occurs concomitantly with DOPC and cholesterol oxidation, as detected by mass spectrometry. In the presence of an oxygen scavenger or an antioxidant, light‐triggered drug release is inhibited, suggesting that the mechanism is related to singlet oxygen mediated oxidization of unsaturated lipids. Despite the irreversible modification of lipid composition, DOPC‐containing PoP liposome permeabilization is transient. Human pancreatic xenograft growth in mice is significantly delayed with a single chemophototherapy treatment following intravenous administration of 6 mg kg−1 doxorubicin, loaded in liposomes containing small amounts of DOPC and PoP. Light‐triggered drug release has attracted attention as a means to enhance chemophototherapy approaches to treat solid tumors. It is shown that when drug‐loaded and non‐PEGylated liposomes contain both unsaturated and photoactive lipids, release triggered by near infrared light is greatly accelerated. The mechanism is related to oxidation of the unsaturated lipids.