In vivo targeting of surface-modified liposomes to metastatically growing colon carcinoma cells and sinusoidal endothelial cells in the rat liver

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Abstract
We prepared immunoliposomes by covalent coupling of a randomly thiolated monoclonal antibody against the rat colon adenocarcinoma cell line CC531 to MPB-PE on the outer surface of conventional as well as PEGylated liposomes of about 100-nm diameter. We attempted to target these immunoliposomes in vivo to CC531 cells growing metastatically in the liver of syngeneic rats. Only when the immunoliposomes contained PEG-DSPE, did we observe, both with fluorescent and radioactive labels, accumulation of label in many, but not all, metastatic nodules. The fluorescent label concentrated in scattered areas within the nodules. By means of transmission electronmicroscopy, using colloidal gold particles as an encapsulated morphological marker, we established that the large majority of the tumor-associated gold particles located in areas not containing tumor cells. Most of the gold was detected in cells with a macrophage morphology. We tentatively ascribe this to either tumor morphology or to the coupling procedure we applied for the preparation of the immunoliposomes, or both. The random thiolation step of the antibody molecule conceivably allows for the exposure of the Fc portion of (part of) the antibody molecules so as to permit interaction with Fc receptors on the macrophages. Experiments with immunoliposomes prepared either by coupling of the antibody specifically via its Fc portion or by using F(ab')2 fragments are in progress. The crucial condition of liposomal longevity as in the above experiments, where PEG-ylation of the immunoliposomes was necessary in order to achieve accumulation in the tumor area, by no means represents a general requirement for successful liposome targeting. We have shown that for efficient liposome targeting to a cell population which is readily accessible from the circulation, and has a high affinity for the liposomes, i.e. the hepatic sinusoidal endothelial cells, the presence of PEG chains may even be counter-productive.