Untargeted Liposomes Research Articles

Flow cytofluorometric investigation of the uptake by hepatocytes and spleen cells of targeted and untargeted liposomes injected intravenously into mice

Untargeted liposomes (composition: PC-PS-cholesterol) and targeted liposomes (composition: PC-PS-cholesterol-lactosylceramide) having encapsulated concentration-quenched carboxyfluorescein were injected intravenously into mice. 1 h after injection, the mice livers were perfused, excised and the hepatocytes were separated from nonparenchymal cells and analysed in a fluorescence-activated cell sorter analyzer. The result was that hepatocytes took up significantly more liposomes when lactosylceramide was inserted in the liposome bilayers, which was in good agreement with observations made on the in vivo uptake of liposome-encapsulated insulin gene (Soriano, P. et al. (1983) Proc. Natl. Acad. Sci. USA, 80, 7128–7133). Cytofluorimetric analysis of the spleen cells showed that approx. 10% of the splenic lymphocytes take up high amounts of lactosylceramide liposomes, whereas most of the phospholipid liposomes are taken up by the phagocytic cells. The flow cytofluorimetric analysis shows, moreover, the internalization of the liposomes by the target cells and allows a quantitation of this uptake. Thus, in vivo targeting of the liposomes to specific liver and splenic cells, by means of glycolipid insertion in the liposome bilayer, is shown to take place with delivery of the liposomal aqueous space marker to these cells.

Inability of liposome encapsulated 1-β- d-arabinofuranosylcytosine nucleotides to overcome drug resistance in L1210 cells

The uptake, metabolism and antitumor activity of 1-β- d-arabinofuranosylcytosine nucleotides encapsulated in liposomes were investigated in L1210 cells sensitive and resistant to the drug. These studies were carried out in order to determine whether encapsulation of the presumed active component of the drug, namely, arabinofuranosylcytosine 5′ triphosphate will convert resistant cells to sensitive. The results indicate that liposome entrapment of Ara-CMP and Ara-CTP did not result in increased delivery of these metabolites into L1210 cells. The amount of nucleotide found intracellularly following an in vitro incubation of encapsulated drugs with L1210 cells did not exceed the level expected from a simple extracellular breakdown of liposome releasing their contents with subsequent uptake and phosphorylation of the released nucleoside. Further evidence for lack of enhancement of drug uptake by liposome encapsulation were obtained when the rate of incorporation of TdR into DNA of L1210/Ara-C was not significantly affected by Ara-CTP encapsulation in liposome. The data presented herein also demonstrated that the in vivo sensitivity of L1210 cells resistant to Ara-C could not be modified by encapsulation of Ara-CTP in liposomes. The results strongly suggest that encapsulation of drugs unmodified or untargeted liposomes will not be able to overcome drug resistance related to transport defect and/or deletion of intracellular activating enzyme(s).