Silica-Based Nanoparticles for Intracellular Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 352

device to facilitate receptor-mediated endocytosis, e.g. folate groups have proved
to facilitate folate-receptor mediated endocytosis in human cancer cells (Slowing
et al. 2006 ). This will be developed later in this section.

4.2.3 Influence of Surface Functionality

To deliver a drug loaded in silica-based nanoparticles, there are two possible ways
of entry in the cell. The first one is the internalization of the nanoparticles via endo-
cytosis that will require to take into account the endosomal acidic environment and
a strategy for endosomal escape. The influence of surface charge on the ability of
the particles to escape the endosome has already been mentioned but endosomal
escape can also be tuned by grafting different groups on the surface of the nanopar-
ticles, for instance amine containing polymers, that have the ability to buffer endo-
somes thus affecting the osmotic gradient. This will eventually lead to the release
of the endosomal cargo into the cytoplasm (Rosenholm et al. 2009 ). Coating silica
particles with polyethyleneimine is easily and rapidly obtained by adding the par-
ticles to a stirring solution of the polymer in sodium acetate buffer. This polymer
has another interest: amine groups are positively charged at physiological pH, thus
leading to positively charged nanoparticles. As the cell membrane is negatively
charged, a natural affinity between the positive particles and the membrane can lead
to some adherence of the nanoparticles to the membrane, thus enhancing their
internalization.
In vitro studies have also used photochemically-induced endosomal release of
silica nanoparticles (Sauer et al. 2010 ). Here the principle is a little different
because the photosensitizer group (disulfonated porphyrin derivative meso-tetraphenyl
porphine) is not grafted to the particles but incubated with the cells. This molecule
will be endocytosed and bound to the membrane of the endosomes. Under light
irradiation, the molecule is activated and generates a singlet oxygen that will lead
to endosome disruption through oxidation of the different compounds of the mem-
brane. Such a technique could be used for intracellular delivery if enough control
is gained on the targeting of the photosensitizer. Another possibility is a direct
delivery to the cytoplasm using cell-penetrating peptides (e.g. Tat) grafted
to the particles (Santra 2004 ; Mao et al. 2010 ) (Fig. 9 ). The later pathway has
the advantage to avoid any endosomal escape strategy and to possibly preserve the
cargo from the endosome environment. Furthermore, some drug will have to be
delivered specifically to definite organelles to maximize their efficiency and direct
delivery would minimize the loss of bioactivity. Tat peptide can be covalently
grafted via water-soluble carbodiimide reagents onto the surface of carboxyl-coated
silica nanoparticles. One key parameter is to adjust the number of Tat grafted to the
size of the particles. Indeed the bigger the particle, the more peptides will be needed
to permit membrane permeation. Of course, Tat-peptide is not the only cell-
penetrating peptide available and, depending on the peptide, the internalization
mechanism may vary.