ENGINEERING OF CELL-PENETRATING PEPTIDE-CONJUGATED INTRACELLULAR DELIVERY SYSTEMS - Biologically-Responsive Hybrid Biomaterials - page 206

Kwon et al. have developed a modified 'antibody targeted, triggered,
electrically modified prodrug-type strategy' (ATTEMPTS) approach in delivery
of macromolecular drugs, which integrates the cell-penetrating PTDs into a
heparin/protamine-regulated delivery system (Figure 2) [72]. The system consists
of the targeting component (such as antibody), coupled to a heparin molecule.
Fig. 2. Schematics of the CPP-modified ATTEMPTS system.
The drug component (such as the macromolecular drug) is covalently linked
with a PTD peptide such as TAT via a disulfide bond. These two components
spontaneously associate with each other through charge-charge interactions
between the anionic heparin and the cationic TAT. The prodrug feature (i.e. due
to inhibition of the cell-penetrating function by heparin) and targeting moieties
can prevent interaction of the drug complex with normal tissues during tumor-
targeting, thereby alleviating drug-associated toxic effects. Once the TAT-
Drug/Ab-Heparin complexes reach the target, a competing agent such as
protamine sulfate can be administered which binds to heparin with greater
affinity than TAT and thus dissociating the TAT-Drug conjugate from its Hep-
Ab counterpart. Then the TAT-Drug conjugates can be taken up by the targeted
tumor cells. Once inside tumor cells, the drug molecule can be detached from