CTPs first, then CPPs ?

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In this review, we have emphasized the usefulness of CPPs for improving the cellular delivery of different kinds of drugs. However, many experimental results stress that the main setback of CPPs is the absence of specific cellular delivery. Some alternative strategies, often very elegant, have been conceived with encouraging results, although they are mainly applied in very specific cases and rely on the synthesis of sometimes complex molecules. On the other hand, if these tools will reduce significantly the dose which needs to be injected, pharmaceutical companies could become interested in further developing these compounds.

We have then described some peptides that can recognize specific cell types and target these cells (CTPs). When these peptides are coupled to a drug, they specifically target a cell type, however, little is known about the efficiency of this cellular delivery. Moreover, we need also to increase the overall internalization and/or the release from the endosome of CTP-bound molecules, two features which are specific of CPPs. It would be, therefore, interesting to associate the cell specificity of CTPs with the efficient internalization and endosome release of CPPs in a chimerical molecule made with a CTP linked to a CPP. Unfortunately, several examples show that when Tat is coupled to antibodies expected to promote specific cell recognition there is a dramatic loss of specificity. The main problem appears to be the exposure of the CPP to the anionic cellular components of the cells. Ideally, the design of a multi-component delivery system should resemble a structure in which an exposed cell-recognition motif would first favor the concentration of the drug at the targeted cell type. At that point an efficient cell penetrating peptide attached to a payload molecule should be exposed (Figure 2). We mentioned in this review different and efficient strategies for the concentration of drugs at a specific cell type or for the local release of drug-loaded CPP. The main issue will be to combine these cell-targeting and cell-penetrating peptides into the same pharmaceutical unit and to trigger their exposure in the right place and at the right moment.