Targeting of Tlck-Coupled Liposome to Simian Virus 40 Transformed Mouse Fibroblasts
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University of Ghana
Abstract
N-a-tosyl-L-lysyl-chloromethyl ketone (TLCK) has
been coupled to ara-C or colchicine encapsulated liposomes
via glutaraldehyde treated liposomal phosphatidylethanolamine
(Lp-G-TLCK) or sodium metaperiodate oxidized oligosaccharide
side chain of liposomal digoxin (Lp-D-TLCK).
TLCK has been shown to react with specific histidine residue
at the active site of such protein as trypsin and has
high binding affinity for simian virus 40 and polyoma
virus transformed fibroblasts. A 20-minute exposure of
cells to Lp-G-TLCK containing ara-C impaired the growth
of tumor cells (SVT2 ) for up to two days, but did not impair
the growth of normal cells (Balb/C 3T3). However, at
50-minute exposure, the Lp-G-TLCK containing ara-C impaired
the growth of Balb/C 3T3 cells at day one but recovered
by the second day. The SVT2 cells, on the other
hand, did not recover from the cytotoxic effect of Lp-GTLCK,
containing ara-C during the second day. The underivatized
liposome (Lp-PE) containing ara-C was cytotoxic
to both Balb/C 3T3 and SVT2 cells at 20 or 50 minute exposure
periods.
The Lp-D containing ara-C, at 20 to 60-minute exposure,
slightly impaired the growth of SVT2 and Balb/C
3T3 cells at day one. Such cytotoxic effect was, however,
not observed by the second and third days of growth. In
contrast, Lp-D-TLCK containing ara-C impaired the growth
of SVT^ cells while the growth of Balb/C 3T3 cells was
nearly indistinguishable from control cells over a threeday
period. Thus TLCK selectively enhanced ara-C encapsulated
Lp-D-TLCK SVT2 cell cytotoxicity. Lp-D-TLCK containing
colchicine, while impairing the growth of Balb/C
3T3 cells, was particularly cytotoxic to SVT2 cells, indicating
that colchicine may be an unsuitable anti-tumor
drug for use in a culture system with normal cells in
their exponential growth phase.
The uptake of Lp—D—TLCK by SVT2 cells was higher
than the uptake by Balb/C 3T3 cells. With respect to
underivatized liposome (Lp-D) the uptake by Balb/C 3T3
cells was higher than the uptake by SVT2 cells, indicating
that TLCK enhanced liposome reaction with SVT2 cells and
may retard reaction with the Balb/C 3T3 cells.
Description
Thesis (PhD) University of Ghana, 1984