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Disagreement well (figures 5(A)–(B)). However, pre-treatment with

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       Disagreement and the need for further
progress with targeted nanoparticle-mediated drug delivery were emphasized by a
recent review that analyzed data published over the past 10 years and concluded
that only 0.7% (median)
of the administered nanoparticle dose is
found to be delivered to a solid tumor. In this regard, it should be mentioned
that the drug can still be delivered and accumulated in the tumor via other
mechanisms that are directly or indirectly mediated or affected by the
nanoparticles. An example of the latter is passive tumor targeting, also known
as the enhanced permeability and retention
(EPR) effect. EPR can be used at later
stages in tumorigenesis as it relies upon a well-formed tumor vasculature.
However, recently it was demonstrated that ND may induce the improved vascular
permeability independent of tumor-induced EPR219.
Interestingly, among NDs with different but well defined
surface chemistries, ND-NH2 has induced the highest degree of
vascular leakiness compared to ND-COOH and as-received ND. The proposed
mechanism include a ND-triggered cascade of biochemical processes, resulting in
opening of tight junctions between the endothelial cells. This effect is
reversible and the tight junctions are restored to normal when the ND treatment
ceased. The observed ND-triggered endothelial tissue leakiness and its
application to kill the tumor cells were demonstrated in
vitro using the Transwell model. When not treated with ND, the
vascular barrier well protect the cancer cells in the bottom well from
doxorubicin (DOX)
added to the top well (figures 5(A)–(B)).
However, pre-treatment with NDs rendered the vascular barrier transparent to
DOX resulting in a significantly higher cancer cell death rate
(up to 140%) compared to ?6% death rate observed in the control (not
exposed to NDs) vascular barrier model. Due
to its large and fully available surface area (all
external, no pores in contrast to activated carbons),
ND was studied for adsorption and triggered librate for many anticancer drugs, including 4-hydroxytamoxifen,
tetracycline, and paclitaxel220. When
entering the cell in the form adsorbed on ND, the drugs cannot be easily
ejected by cell efflux mechanisms, instead they are
slowly desorbed from ND inside the cell keeping therapeutic concentrations, an
effect that was used to reverse the drug resistance of cancer cells to
traditional chemotherapeutics. Therapeutic efflux
is the most common mechanism for chemoresistance that limits the effectiveness
of cytotoxic drugs. ND-drug complexes
have been shown to bypass the cell protective mechanisms and deliver the
anticancer cargo to the cytoplasm through the endosomal release . The endosomal
liberation is triggered by low pH in the endo-some that give the ND surface
chemistry which have been rationally designed that will favor the desorption of
the drug from ND. Considerably higher IC50 for ND-drug complexes compared to
the drugs alone are associated with sustained release of the drug and are supposed
to be beneficial for clinical use, resulting in lower systemic doses and
protecting systemic apoptosis and
myelosuppression caused by cytotoxic therapy221,222. A large
size of ND-drug complex results in a prolonged retention time in a cancer cell.
For example, ND-epirubicin complex gives a fluorescence
signal inside LT2-MYC cells after 12 h post-treatment as compared to epirubicin
alone or liposomal epirubicin formulation where no fluorescence
was observed after the same period of time. Adsorption on 5 nm ND particles may
also increase bioavailability of poorly soluble drugs, exposing them to a
physiological environment in the form of a molecule-thick monolayer the
finest dispersion state achieved in principle for poorly
soluble molecules.

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