Biomedical Engineering Reference
In-Depth Information
nanomedicines. For example, thiol-maleimide chemistry is a commonly used
linker to attach targeting ligands on the surface of nanoparticles.
19
However,
Junutula and co-workers engineered cysteines into a therapeutic HER2/neu
antibody at three sites differing in solvent accessibility. They found that highly
solvent-accessible sites rapidly lost conjugated thiol-reactive linkers in plasma
owing to maleimide exchange with reactive thiols in albumin, free cysteine, or
glutathione.
60
d
n
4
y
3
n
g
|
0
2.3.2 Increased Clearance of Active Targeting Nanomedicines
Several recent studies have shown that the presence of targeting ligands such as
folate, peptide, and antibodies on the surface of nanomedicines can decrease
their blood circulation times.
53,61,62
This is not unexpected, since a prolonged
circulation time of nanomedicines is a result of the shielding hydrophilic
polymer (e.g., PEG). When targeting ligands are conjugated on the distal end
of the PEG chain, they sometimes result in recognition by the RES, with
accelerated clearance by the liver.
63
Our previous study found that cRGD-
encoded and cRGD-free superparamagnetic polymeric micelle (SPPM)
formulations had comparable a-phase plasma half-lives (t
1/2
,
a
) at 0.34 ¡
0.09 and 0.40 ¡ 0.34 h, respectively. However, cRGD-free SPPM had a
significantly slower clearance in the b-phase, as represented by longer t
1/2,b
(9.2
¡ 0.8 h) than cRGD-encoded SPPM (3.9 ¡ 0.8 h). We attribute this variation
to the different functionalization of peptides (i.e., cRGD vs. Cys) on the SPPM
surface.
64
McNeeley et al. reported that adding just 0.15% folate to PEGylated
liposomes significantly reduced the t
1/2
value from 18 to 6.7 h.
62
Nie and co-
workers also reported that three types of peptide-coated gold nanoparticles
had significantly shorter t
1/2
than nontargeted nanoparticles.
65
Clearly, the
density of targeting ligands needs to be optimized to provide prolonged blood
circulation times for tumor accumulation while allowing for cancer-specific
receptor targeting to increase uptake in cancer cells.
2.3.3 Tumor Accumulation: Passive vs. Active Targeting
Nanomedicines
There are still considerable debates on the relative contributions of active and
passive targeting to the targeting efficiency and antitumor efficacy of
nanoparticles to the tumor tissues and cancer cells.
66
Results from several
research groups suggested that cancer-specific nanomedicines help improve the
delivery efficiency of anticancer drugs, with increased dose accumulation at
tumor sites compared to control nanoparticles lacking targeting ligands.
62,67
In
contrast, several other groups have shown that the use of tumor-targeting
ligands did not increase the total accumulation of nanoparticles in solid
tumors, although it did increase receptor-mediated internalization in cancer
cells.
42,48,54
In other words, active targeting may play a larger role in
facilitating increased cellular uptake of nanomaterials than in increasing tumor
