Intracellular Delivery: A Multifunctional and Modular Approach - Intracellular Delivery: Fundamentals and Applications - page 213

Cell

Antigen

Cell

Long PEG
spacer

Antibody

CPP

Short PEG
spacer

Low pH
inside tumor

Longer PEG
spacer

pH sensitive
bond

Fig. 8 The principle scheme of the action of stimuli-sensitive double-targeted nanocarriers. The
surface of the nanocarrier is modified with a CPP via a relatively short spacer; with longer PEG
chains; and with even longer PEG chains decorated at distal termini with a target-specific ligand
(antibody). CPP is shielded with longer chains, while these PEG chains and PEG-antibody chains
are attached to the surface via pH-sensitive bonds. The whole system is stable in the blood and
accumulates in the tumor via the PEG-mediated EPR effect and via antibody-mediated targeting.
Inside the tumor, protective PEG chains and PEG-antibody conjugates are detached from the
surface because of fast hydrolysis of pH-sensitive bonds at the lowered intratumors pH, CPP
becomes exposed and allows for the intracellular delivery

was assessed after 72 h. The administration of pGFP-TATp-liposomes with a
non-pH-sensitive PEG coating resulted in minimal transfection of tumor cells
because of steric hindrances for liposome-to-cell interaction created by the PEG coat,
which shielded the surface-attached TATp. The administration of pGFP-TATp-lipo-
somes with the low pH-detachable PEG resulted in the highly efficient transfection.
The removal of PEG under the action of the decreased intratumoral pH led to the
exposure of the liposome-attached TATp residues, enhanced penetration of the lipo-
somes inside tumor cells and more effectively delivered the pGFP intracellularly
(Fig. 9b ) (Kale and Torchilin 2007b ).
TATp-modified stimuli-sensitive polymeric micelles with an enhanced ability to
interact with cells under acidified conditions have also been described in (Sethuraman
and Bae 2007 ). These results can be considered as an important step in the develop-
ment of tumor-specific stimuli-sensitive drug and gene delivery systems.

4 Subcellular Targeted Nanocarriers

The next step in the development of targeted nanocarriers would be designing of
subcellular or organelle targeted nanocarriers to target at molecular receptor level
(Rajendran and Knolker 2010 ; D'Souza and Weissig 2009 ; Torchilin 2006 ). Our
focus has been on the development of nanocarrier systems targeted to mitochondria
and lysosomes.