The aim of the present study was to characterize the interactions of
antagonist G (H-Arg-D-Trp-N(me)Phe-D-Trp-Leu-Met-NH 2)-targeted sterically stabilized
liposomes with the human variant
small cell lung cancer (SCLC) H82 cell line and to evaluate the antiproliferative activity of encapsulated
doxorubicin against this cell line. Variant SCLC
tumors are known to be more resistant to
chemotherapy than classic SCLC
tumors. The cellular association of
antagonist G-targeted (radiolabeled)
liposomes was 20-30-fold higher than that of non-targeted
liposomes. Our data suggest that a maximum of 12,000
antagonist G-targeted
liposomes were internalized/cell during 1-h incubation at 37 masculine C. Confocal microscopy experiments using
pyranine-containing
liposomes further confirmed that receptor-mediated endocytosis occurred, specifically in the case of targeted
liposomes. In any of the previously mentioned experiments, the binding and endocytosis of non-targeted
liposomes have revealed to be negligible. The improved cellular association of
antagonist G-targeted
liposomes, relative to non-targeted
liposomes, resulted in an enhanced nuclear delivery (evaluated by fluorimetry) and cytotoxicity of encapsulated
doxorubicin for incubation periods as short
as 2 h. For an incubation of 2 h, we report IC50 values for targeted and non-targeted
liposomes containing
doxorubicin of 5.7 +/- 3.7 and higher than 200 micro M
doxorubicin, respectively. Based on the present data, we may infer that receptors for
antagonist G were present in H82
tumor cells and could mediate the internalization of
antagonist G-targeted
liposomes and the intracellular delivery of their content.
Antagonist G covalently coupled to liposomal drugs may be promising for the treatment of this aggressive and highly heterogeneous disease.