Local CPP-mediated delivery − Rakyat Biologi

The apparent in vivo “spreading” of CPP-coupled molecules could be circumvented if the chimerical constructs could be applied directly on the targeted cells, or at least in their close vicinity. Local application of CPPs could be compared to an in vitro experiment. This has been performed, for instance, with an arginine homopolymer to vectorize cyclosporine A into the skin [87]. In this study, crossing of the stratum corneum and diffusion into the epidermis was observed, although fixation artifacts were not considered at that time. This chimera entered a phase II clinical trial in 2003 for the treatment of psoriasis under the commercial name of PsorBan®. However, despite an efficient uptake of the chimera, the release of the free drug was not rapid enough to compete with clearance (P.A. Wender, personal communication). Local delivery of drugs through a CPP has been attempted also in the vitreous body and in the sub-retinal space of the eye following intraocular injection of CPPs [88]. In such a situation, any diffusion of the CPPs is obviously strongly reduced.

Intracoronary injections of a Tat-delta protein kinase C inhibitor chimera (KAI-9803) have also been used for the treatment of acute myocardial infarction [89]. In addition to local intracoronary administration, KAI-9803 just commenced in March 2007 an intravenous phase 1 clinical study.

Moreover, delivery to the lungs of siRNAs bound to CPPs has been also described [90]. Indeed, topical delivery to lungs is facilitated by either intranasal, intratracheal or aerosol administration (for a recent review [91]). In the study by Moschos and colleagues, a siRNA designed to turn off the expression on an intracellular protein (the p38 MAP kinase) was conjugated through a disulfide bridge to Antennapedia or Tat peptides. A 30 to 45% knockdown of the corresponding RNA was recorded at 6h post-administration. However, and rather unexpectedly, higher doses of the chimera did not induce a stronger response. It is also noteworthy to point out that Tat and Antennapedia-coupled siRNAs induce different cellular responses, reflecting apparently a different intracellular fate of these two conjugates [90], as already mentioned in another study [92].