Biomedical Engineering Reference
In-Depth Information
6.4.2 P
HYSICOCHEMICAL
F
ACTORS
I
NFLUENCING
B
IODISTRIBUTION
OF
P
ARTICULATE
D
RUG
C
ARRIERS
6.4.2.1 ParticleSize
The size of the particulate drug carriers has been proved to be a primary key in determining their
biodistribution. Particulate drug carriers with a lower size range are preferable than those in the
upper submicron and micron sizes to achieve longer circulation half-lives (reduced MPS uptake)
and more effi cient celluar uptake (increased internalization) [23]. Generally, particles less than 1 µm
generate a phagocytic response. Koval et al. investigated the uptake and transport of IgG-opsonized
polystyrene beads of defi ned size ranging from 0.2 to 3 µm into murine macrophages. They found
that phagocytosis uptake was size dependent; more than 30% of 0.2-0.75 µm particles compared
with less than 80% of 2-3 µm particles were taken up [73]. Particulate drug carriers should also not
exceed 200 nm to prevent substantial entrapment by hepatic and splenic endothelial fenestrations
and subsequent clearance [72].
In addition, cellular internalization of drug-loaded particles is likely to play a key role in deter-
mining their biological activity. Intracellular uptake of particles can occur by various mechanisms
according to the uptake by phagocytic cells, nonphagocytic cells, and drug-resistant cancer cells. The
molecular mechanisms mediating the internalization of particles are dependent on the size of the
particles. Particles as large as 500 nm can be internalized by nonphagocytic cells through an energy-
dependent process, which is inhibited by drugs that affect membrane vesicle formation. Smaller
particles with a diameter of less than 200 nm are internalized through clathrin-coated pits, while
larger particles are internalized through caveole membrane invaginations [14]. Rejman et al. showed
that as particle size increased, internalization was decreased. There was no cellular uptake of par-
ticles when they are above 500 nm in size [74]. Tabata and Ikada reported that
in vitro
phagocytosis
of polystyrene and polyacolein microspheres by mouse peritoneal macrophages was maximum
when the particles were between 1.0 and 2.0 µm in size. When the particle size is reduced below
100 nm, concentration of the carrier can occur in the bone marrow for both radiopharmaceuticals
and liposomes [49]. Chemotherapy with small-sized nanoparticles was performed in tumor-bearing
animals. Taxol-incorporated polyvinylpyrrolidone nanoparticles with a diameter of 50-60 nm were
assayed on a B16F10 murine melanoma transplanted subcutaneously in mice. Mice treated with
repeated intravenous injections of taxol-loaded nanoparticles showed a signifi cant tumor regression
and higher survival rates than mice treated with free taxol [75].
6.4.2.2 SurfaceHydrophobicity
The surface characteristics of particulate drug carriers are also the key for the biological fate
of nanoparticles. The importance of surface hydrophobicity in the pathogenicity of bacteria
was clearly illustrated by Van Oss and Absolom. If the contact angles (a measure of surface
hydrophobicity) were less than those for neutrophils, then phagocytosis was avoided, whereas
a more hydrophobic surface led to sequestration. In addition to affecting the extent of ingestion
of nonopsonized bacteria, the surface hydrophobicity will also strongly infl uence the degree of
nonspecifi c IgG adsorption and compartment activation, which promote phagocytic uptake in
serum. The adsorption of dysopsonic IgA, however, increased the surface hydrophilicity and hence
decreased phagocytosis [49].
Thus, nanoparticles can be coated with biodegradable matrices and become invisible to
macrophages. Since the usefulness of conventional nanoparticles is limited by their massive capture
by the macrophages of the MPS after intravenous administration, other nanoparticulate devices
must be considered to target tumors, which are not localized in the MPS area. Recently, a great deal
of work has been devoted to develop so-called Stealth particles, which are invisible to macrophages.
These Stealth nanoparticles are characterized by a prolonged half-life in the blood compartment.
This property allows them to selectively extravasate in pathological sites like tumors or infl amed
