ENGINEERING OF CELL-PENETRATING PEPTIDE-CONJUGATED INTRACELLULAR DELIVERY SYSTEMS - Biologically-Responsive Hybrid Biomaterials - page 212

the leaky vasculature (tumors and infarcts) by the enhanced permeability and
retention (EPR) effect [111-114]. The active targeting can be achieved by
attachment of target-specific molecules to their surface [111, 112].
Micelles made of PEG-phosphatidyl ethanolamine (PEG-PE) can provide
additional advantages for particle stability when compared with conventional
amphiphilic polymer micelles due to the existence of two fatty acid acyls, which
might contribute considerably to an increase in the hydrophobic interactions
between the polymeric chains in the micelle core [115]. PEG-PE micelles
demonstrate good stability, longevity, and ability to accumulate in the areas with
damaged vasculature (EPR effect in leaky areas, such as infarcts and tumors)
[115, 116]. Both liposomes and micelles can be easily modified with CPP. Some
possible ways to attach CPP to micelles and liposomal surfaces is shown in
Figure 3.
Fig. 3. CPP attached to liposomes and micelles by the insertion into the hydrophobic phase of
liposome membrane or micelle inner core via spacer arm (linker) with hydrophobic “anchor”.
TATp (47-57)-modified liposomes were delivered intracellularly in different
cells, such as murine Lewis lung carcinoma (LLC) cells, human breast tumor
BT20 cells, and rat cardiac myocyte H9C2 cells [117]. Liposomes were modified
with TATp via para -nitrophenyl (pNP) groups at the distal ends of the liposome
containing pNP-PEG-PE. The preparations of TATp-liposomes, which allowed
for the direct contact of TATp residues with cells, displayed an enhanced uptake
by the cells. This suggested that the translocation of TATp-liposomes into cells
require direct free interaction of TATp with the cell surface. Further studies on
the intracellular trafficking of rhodamine-labeled TATp-liposomes loaded with
FITC-dextran, revealed that TATp-liposomes remained intact inside the cell
cytoplasm within 1 h of translocation, after 2 h they migrated into the perinuclear
zone, and at 9 h the liposomes disintegrated there [118]. It was found that the