Silica-Based Nanoparticles for Intracellular Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 335

vectors: colloidal stability, biocompatibility, long-term circulation, specific targeting,
drug loading and release,…In parallel, an impressive set of data related to the inter-
actions of particles with cells in vitro and, to a lesser extent, related to their in vivo
fate has been accumulated, that are necessary before any clinical studies, not to
mention practical applications, can be foreseen.
This is the scope of this chapter to provide the readers with an up-to-date over-
view of these progresses from a chemical perspective. A first section gathers some
key information about the synthesis and physico-chemical properties of silica-
based nanoparticles. The current knowledge about in vitro and in vivo behavior of
these particles is also presented. A second section describes the different chemical
strategies that have been developed to turn silica nanoparticles into drug carriers. In
the context of the present book, a third section is specifically dedicated to intracel-
lular delivery. As a conclusion, some current fundamental and practical challenges
in this area are presented and critically discussed.

2 Silica-Based Nanoparticles: Synthesis and Reactivity

in Biological Conditions

2.1 The Chemistry of Silica

The process of silica formation from solution occurs following an inorganic polym-
erization reaction (Iler 1979 ). Two monomers, silicic acid Si(OH) 4 , condense with
each other to form a Si-O-Si siloxane bond, giving rise to the (OH) 3 -Si-O-Si-(OH) 3
dimers with departure of a water molecule. As polymerization proceeds, higher
oligomers are formed, with a strong tendency to form cyclic species. The reaction
continues until particles, 2-3 nm in diameter are formed. These particles consist of
hydrated silica with low condensation degree ( i.e . with internal porosity). The pK a
of polysilicic acid is ca . 6 so that the surface of the particle is negatively charged
above pH 3, consisting of silanol Si-OH and silanolate Si-Si-O- groups. If silica
formation occurs near pH 3, these particles bear a low surface charge and tend to
aggregate, forming in many cases a silica gel. Otherwise, these particles continue
to grow either by further monomer addition or by flocculation, but, at any time of
this process, percolation can occur, forming a gel again. Only above pH 8, where
surface charge is high enough, do stable silica particles can be obtained.
However, the condensation reaction is always balanced by the reverse reaction,
i.e. hydrolysis (Icopini et al. 2005 ). This reaction is also pH dependent as it is
favored in the presence of silanolate (Vogelsberger et al. 1992 ). Thus at pH 9 or
above, dissolution is largely favored over condensation, preventing silica formation
but the latter process becomes predominant below this value. Indeed, this equilib-
rium is reflected in silica solubility and is therefore temperature-dependent. For
instance, in pure water near neutral pH, amorphous silica solubility is ca . 50 ppm
at 10°C and ca . 130 ppm at 25°C. In parallel, the reaction kinetics are also influenced