Biomedical Engineering Reference
In-Depth Information
whether gene delivery may also be targeted to neovasculature by coupling lipid-based cationic
nanoparticles to integrin α
V
β
3
targeting ligands in tumor-bearing mice. Nontargeted nanoparticles
showed limited expression (
0.5 ng/g tissue) in tumor, lung, and heart. For targeted nanoparticles,
signifi cant expression was found in the tumor (4 ng/g tissue) and no expression in the lung, liver, or
heart [100]. Systemic injection of the cationic nanoparticles coupled with integrin α
V
β
3
targeting
ligands resulted in apoptosis of the tumor-associated endothelium, ultimately leading to tumor cell
apoptosis and sustained regression of established primary and metastatic tumors [99].
Although the combination of traditional chemotherapy with anti-angiogenesis agents that
inhibit blood vessel growth is an emerging model for effective cancer treatments, the implementa-
tion of this approach has two major obstacles. First, the long-term shutdown of tumor blood vessels
by the antiangiogenesis agent can prevent the tumor from receiving a therapeutic concentration
of the chemotherapy agent. Second, inhibiting blood supply drives the intratumoral accumulation
of hypoxia-inducible factor-1α (HIF1-α). Overexpression of HIF1-α is correlated with increased
tumor invasiveness and resistance to chemotherapy. Recently, Sengupta et al. developed “nanocell,”
which is composed of nuclear nanoparticles within an extranuclear PEGylated lipid envelope that
is preferentially taken up by the tumor [101]. The nanoparticles enable a temporal release of two
drugs: the outer envelope fi rst releases an anti-angiogenesis agent, causing a vascular shutdown, and
the inner nanoparticles, which are trapped inside the tumor, release a chemotherapy agent. They
demonstrated that the focal release within the tumor results in an improved therapeutic index with
reduced toxicity [101].
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6.5.4
I
N
V
IVO
S
TUDIES
WITH
N
ANOPARTICULATES
FOR
T
ARGETED
C
HEMOTHERAPY
Animal tests are critical in determining whether the nanoparticles under a specifi c design for drug
loading could be feasible for clinical administration. Several factors for
in vivo
application that
should be considered in the selection of materials and fabrication of nanoparticles are [2,15-18]
(1) biocompatibility of particles and coatings, (2) particle size, (3) immunogenicity, (4) surface
properties, (5) degradation properties, (6) drug-loading effi ciencies, (7) release characteristics, and
(8) stability of the drug and fabricated nanoparticles.
The overall therapeutic effects of the system can be determined from plots of the plasma drug
concentration versus time. Nanoparticle formulation of the tested drug should be evaluated in com-
parison with the free drug formulation [3]. Yoo et al. conducted
in vitro
and
in vivo
experiments
for controlled release of doxorubicin-loaded PLA nanoparticles.
In vivo
antitumor activity assay
showed that a single injection of the nanoparticles had comparable activity with that of free doxoru-
bicin administered by daily injection [104]. Lu et al. investigated the pharmacokinetics of paclitaxel
released from long-circulating solid lipid nanoparticles (SLN) in kunming (KM) mice. They found
that the nanoparticles exhibited great advantages over the Cremorphor formulation of paclitaxel,
with half-lives of 10.06 and 4.88 h, respectively; in comparison, the half-life for the Cremorphor
formulation of paclitaxel was 1.36 h [105].
Kim et al. evaluated the
in vivo
distribution of various self-assembled nanoparticles in tumor-
bearing mice in order to investigate the mechanisms underlying tumor targeting. Fluorescein
i s o t h i o c y a in a t e - c o in j u g a t e d g l y c o l c h i t o s a in in a in o p a r t i c l e s w e r e p r e f e r e in t i a l l y l o c a l i z e d i in p e r i v a s c u l a r
regions, implying extravasation to the tumor through the hyperpermeable tumor vasculature. They
showed that the magnitude and pattern of tumoral distribution of self-assembled nanoparticles were
infl uenced by several factors such as
in vivo
colloidal stability, particle size, intracellular uptake of
nanoparticles, and tumor angiogenesis [106]. Hashida et al. showed that a sixth generation lysine
dendrimer-conjugated PEG exhibited higher retention in blood and lower accumulativeness in
organs depending on the rate of polyethlyene glycolation than did intact lysine dendrimer [107].
Yang et al. developed the folate-conjugated block copolymeric nanoparticles containing doxo-
rubicin for targeted delivery [108].
In vivo
experiments conducted in a 4T1 mouse breast cancer
model demonstrated that DOX-loaded micelles had a longer blood circulation time than free DOX
