Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes

Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near infrared (NIR) light induced release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e. in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound both to MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared to analogous neutral liposomes, strong tumor photo-ablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm² NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent anti-tumor phototherapeutic effects as the drug loaded ones. A more balanced chemo- and photo- therapeutic response was subsequently achieved when anti-tumor studies were repeated using higher drug dosing (7 mg/kg Dox) and an ultralow fluence phototreatment (20 J/cm² NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations.

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