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

Abstract

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), accelerated near infrared (NIR) light-triggered release in porphyrin-phospholipid (PoP) liposomes by an order of magnitude. In physiological conditions in vitro, 90% of the loaded drug could be released in a minute with NIR irradiation, while liposomes maintained serum stability in the absence of NIR irradiation. This enabled rapid laser-induced drug release using remarkably low amounts of PoP (i.e. 0.3 molar percent). Light-triggered drug release occurred 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 was inhibited, suggesting the light triggered release mechanism was caused by singlet oxygen mediated oxidization of unsaturated lipids. Despite the irreversible modification of lipid composition, DOPC-containing PoP liposome permeabilization was transient. Human pancreatic xenograft growth in mice was significantly delayed with a single chemophototherapy treatment following intravenous administration of 6 mg/kg doxorubicin, loaded in liposomes containing small amounts of DOPC and PoP.

Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes

“…1B. We recently demonstrated that unsaturated lipids such as DOPC can significantly enhance the light triggered release rate due to PoP-dependent unsaturated lipid photo-oxidation (42). Since DOTAP is also an unsaturated lipid and structurally similar to DOPC, we hypothesized that the mechanism of enhanced light-triggered release was related to oxidation of DOTAP.…”

“…We previously demonstrated that the amount of PoP in the formulation will also affect the light-triggered cargo release rate (34,42). By using singlet oxygen sensor green (SOSG), the amount of singlet oxygen generated were determined with liposomes containing various amounts of PoP.…”

“…The porphyrin-phospholipid (PoP) used was sn-1-palmitoyl, sn-2-pyropheophorbide phosphtatidylcholine and was synthesized as previously reported (32). Various formulations were prepared by hot ethanol injection followed by pressurized extrusion as previously described (34,42). The finalized cationic PoP liposome formulation was [DSPC:DOTAP:Cholesterol:PoP], [38:20:40:2] (mol.…”

“…For oxidation inhibition study, sample were irradiated in PBS containing 25 mM sodium sulfite. 1 mL of each liposome sample was then extracted with methanol:chloroform 1:2 (v/v) solution as previously described (42). The extracted lipids were then dried under vaccum and stored at -80 °C before analysis.…”

Liposomal Nanoformulations as Current Tumor-Targeting Approach to Cancer Therapy

“…Another study reported the incorporation of an unsaturated phospholipid, such as dioleoylphosphatidylcholine (DOPC), in order to accelerate the near-infrared light-triggered DOX release in porphyrin-phospholipid liposomes. The formulation inhibited human pancreatic xenograft growth in mice following a single intravenous administration of 6 mg kg −1 DOX, loaded in liposomes [65].…”