C O M M U N I C A T I O N S
(control) were separately applied (0.5 mM) to the back of a nude
mouse, and the residual solution was removed after 30 min. After
a 2 h interval, dissected sections of the treated areas of skin were
exposed to fluorescein-labeled streptavidin. While biotin alone did
not penetrate the skin (Figure 2, panel A), visualization of skin
treated with biotin-transporter 9 (panel C) revealed highly efficient
penetration across the cornified layer of the epidermis and into all
layers of the skin. Nuclear localization (consistent with the known
polycationic nuclear localization signal) was dramatic in the
intensely stained epidermis, and the various cells of the dermis were
also highly stained (detail in Supporting Information).
In conclusion, the oligocarbamate transporters are found to be
among the most efficient molecular transporters studied to date.
They enable exceptionally efficient uptake into cells of a cargo
that by itself does not enter cells. Significantly, they also enable
uptake into skin of a probe molecule that by itself does not penetrate
skin. Structurally these are the first nonamide linked oligoguanidine
transporters and the first with a 1,6-spacing of side chains. The
relationship of these structural features to transport efficiency and
mechanism and the utility of these agents in drug delivery are
subjects of ongoing studies.
Figure 1. FACS determined cellular uptake of oligocarbamate transporters
6-8 and the corresponding fluoresceinated 5-, 7-, and 9-mers of D-arginine
(D-arg5, D-arg7, D-arg9). Jurkat cells were incubated with transporter for 3
min at 23 °C.
Acknowledgment. Support of this work by grants from the
National Institutes of Health (CA 31841, CA 31845) and a CellGate
Fellowship to T.C.J. is gratefully acknowledged.
Supporting Information Available: Experimental data for the
synthesis and biological evaluation of oligocarbamate transporters
(PDF). This material is available free of charge via the Internet at
Figure 2. Uptake into mouse skin. Biotin and biotin-transporter conjugate
9 visualized with streptavidin-FITC (panels A and C). Skin architecture
visualized with propidium iodide counter stain (panels B and D).
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