Biomedical Engineering Reference
In-Depth Information
regions with leaky vasculature. As a result, such long-circulating nanoparticles are supported to
directly target most tumors located outside the MPS region [28].
Tabata and Ikada showed a greater uptake of hydrophobic microspheres compared with
hydrophilic microspheres. Extensive investigations have reinforced the apparent link between the
in
vitro
surface hydrophobicity and a diminished ability to avoid phagocytic sequestration for a range
of surface-modifi ed polystyrene and poly(methylmethacrylate) particles [49]. Hydrophilic coatings
are dextran, PEG, polyethylene oxide (PEO), poloxamers and poloxamines, and silicones. PEG
coating resulted in enhanced circulation time of the particles and reduced opsonization. Ishiwata et
al. showed that PEG coating resulted in suppression of macrophage interaction [2].
Despite these interesting results, the second strategy consisting of the covalent linkage of amphi-
philic copolymers is generally preferred for obtaining a protective hydrophilic cloud on nanopar-
ticles, as it avoids the possibility of rapid coating desorption upon dilution or after contact with the
blood components. This approach has been employed with amphiphilic copolymers like PLA, PCL,
and poly(cyanoacrylate) polymers, which were chemically coupled to PEG [2,28].
6.4.2.3 SurfaceCharge
The role of surface charge in infl uencing protein (fi brinogen) adsorption and thus the surface nature
of polyamide microcapsules was investigated by Kondo. However, the underlying mechanism was
not fully understood, and the evidence for the infl uence of surface charge on particulate uptake has
appeared confusing and often contradictory [49].
Juliano and Stamp [76] reported that the rate of hepatic removal of liposomes was greater when
they were negatively charged rather than when they were positively or neutrally charged. However,
Park et al. suggested that while some negatively charged liposomes can increase liver and spleen
uptake, others could actually avoid uptake leading to prolonged circulation time [49]. Tabata and
Ikada showed no differences between negatively and positively charged particles if they had the
same absolute value [77]. The same authors also demonstrated that for cellulose microspheres, the
extent of phagocytosis increased with increasing negative zeta-potential values [49].
This confusion may refl ect the fact that changes in surface charge are also likely to alter other
surface properties, such as hydrophobicity, which also infl uence the opsonization process [49].
6.4.3 D
ESIGN
OF
L
ONG
-C
IRCULATING
N
ANOPARTICLES
: PEO-M
ODIFIED
N
ANOPARTICLES
There are several reasons why the search for macrophage-evading or long-circulating particles is
so extensive [72]. An important reason is to provide a long-circulating drug reservoir from which
the drug can be released into the vascular compartment in a continuous and controlled manner.
Candidate drugs and therapeutic agents may be those with short elimination half-lives. Therefore,
the requirements in terms of drug release from a long-circulating carrier will depend on clearance
kinetics of the system as well as a pharmacologically desired free drug profi le [72].
During the last 20 years, extensive studies have been carried out on various particulate carriers
to serve as long-circulating systems by reducing the uptake by the cells of RES to rapidly remove
intravenously applied particulates from the systemic circulation [75].
As mentioned in Section 6.4.2, it has been repeatedly emphasized that the clearance behavior
and tissue distribution of intravenously injected particulate drug carriers are greatly infl uenced
by their size and surface characteristics [72]. These physicochemical parameters can control the
degree of particle self-association in the blood as well as particle association. The size of particle
may change substantially upon introduction into a protein-containing medium (e.g., plasma). Thus,
particles and their aggregates should be small enough so that they are not removed from the circula-
tion by simple fi ltration in the fi rst capillary bed encountered.
The concept of surface modifi cation of particulate carriers to control the opsonization process
and the specifi c interaction of particulate carriers with phagocytic cells as well as the nonspecifi c
