DIPLASMENYLCHOLINE-FOLATE LIPOSOMES - AN EFFICIENT VEHICLE FOR INTRACELLULAR DRUG-DELIVERY

Most pharmaceutical and gene therapy applications of targeted liposome s Presently suffer from inefficient contents delivery to the cytoplasm of target cells. We report a plasma-stable liposome, composed of synt hetic, naturally occurring diplasmenylcholine -O-(Z-1'-hexadecenyl)-sn -glycero-3-phosphocholine; DPPlsC), that rapidly and efficiently relea ses its contents at endosomal pHs. Acid-catalyzed hydrolysis of these Liposomes produces glycerophosphocholine and fatty aldehydes, leading to greatly enhanced liposome permeability (t(50% release) congruent to 1-4 h between pH 4.5-5.5) when >20% of the vinyl ether lipid has been hydrolyzed; Plasma stability of nonhydrolyzed 9:1 DPPlsC/dihydrochole sterol liposomes exceeds 48 h at 37 degrees C, pH 7.4 in 50% serum; pu re DPPlsC liposomes remain stable in 10% serum under the same conditio ns. Fluorescence assays of KB cells treated with 99.5:0.5 DPPlsC/DSPE- PEG3350-folate liposomes containing encapsulated propidium iodide (PI) indicate that 83% of the PI escapes the endosomal compartment within 8 h to produce intensely stained nucleii. The IC50 value of 1-beta-ara binofuranosylcytosine (Ara-C) encapsulated in DPPlsC/DSPE-PEG3350-fola te liposomes is 0.49 mu M in KB cell cultures, a similar to 6000-fold enhancement in cytotoxicity compared with free drug (2.8 mM), Empty DP PlsC/DSPE-PEG3350-folate liposomes had no effect on DNA synthesis, ind icating that DPPlsC and its degradation products are benign to cell fu nction at these lipid concentrations. Our results suggest that concurr ent application of selective targeting and membrane translocation mech anisms in drug carriers can significantly increase their efficacy.