Biomedical Engineering Reference
In-Depth Information
localization.
68
Choi et al. found that the accumulation in tumors and other
organs of PEGylated gold nanoparticles decorated with various amounts of
human transferrin (TF) were independent of TF in mice bearing s.c. Neuro2A
tumors at 24 h after i.v. tail-vein injections.
42
Park and co-workers also found
that antibody-directed targeting did not increase the tumor localization of
immunoliposomes, as both targeted and nontargeted liposomes achieved
similarly high levels (7-8% injected dose/g tumor tissue) of tumor tissue
accumulation in HER2-overexpressing breast cancer xenografts (BT-474).
50
These debates point to the necessity to fundamentally understand the
spatiotemporal patterns of active targeting nanomedicines and their depend-
ence on the pathophysiology of the tumor microenvironment. Our recent
studies revealed that cell targeting efficiency and tumor accumulation of
cRGD-encoded superparamagnetic polymeric micelles (SPPM) to a
v
b
3
-
expressing angiogenic tumor vasculature in A549 tumor-bearing mice are
highly dependent on time. Time-resolved MRI data clearly demonstrate that
increased tumor accumulation of cRGD-encoded SPPM was observed at the
vascular ''hot spots'' in tumors in the first 30 min after SPPM injection.
69
This
is further corroborated by tissue distribution studies using
3
H-labeled SPPM,
where a two-fold increase of nanoparticle accumulation was observed for
cRGD-encoded SPPM over the nontargeted control at 60 min post-injection.
64
However, the accumulation of the cRGD-encoded SPPM did not show any
significant differences compared to the cRGD-free SPPM in A549 tumor
xenograft after 24 h (unpublished results). Presumably, we hypothesize that
the longer circulation times of cRGD-free SPPM compensated for the tumor
accumulation at longer times (e.g., 24 h) via the passive targeting effect despite
the short-term advantage of the active targeting nanoparticles. Similar
compromises may also exist in folate and other targeted nanoparticles.
62,65
The temporal dependence of cell targeting and/or tumor accumulation of
passive vs. activate targeting nanomedicines indicates much more careful
investigation is necessary to evaluate their therapeutic contributions in cancer
chemotherapy.
d
n
4
y
3
n
g
|
0
2.4 Conclusion and Future Perspectives
Although small molecular drugs are the mainstay of chemotherapy for cancer
treatment, they suffer many limitations such as nonspecific tissue distribution,
fast clearance from blood, and high acute toxicity. Nanomedicines are
emerging as a powerful platform with integrated optimization of drug
pharmacokinetics and pharmacodynamics for cancer therapy. Passive tumor
targeting through the EPR effect has substantially improved therapeutic
efficacy and increased the amount of drugs at tumor sites. Moreover,
nanomedicines that can actively target cell-surface receptors with high affinity
and cancer specificity have the potential to be most efficacious as the next
generation of personalized medicines for cancer therapy. However, molecular
and phenotypic heterogeneity is a significant challenge since not all cells within
