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

       Disagreement and the need for furtherprogress with targeted nanoparticle-mediated drug delivery were emphasized by arecent review that analyzed data published over the past 10 years and concludedthat only 0.7% (median)of the administered nanoparticle dose isfound to be delivered to a solid tumor. In this regard, it should be mentionedthat the drug can still be delivered and accumulated in the tumor via othermechanisms that are directly or indirectly mediated or affected by thenanoparticles. An example of the latter is passive tumor targeting, also knownas the enhanced permeability and retention(EPR) effect. EPR can be used at laterstages in tumorigenesis as it relies upon a well-formed tumor vasculature.

However, recently it was demonstrated that ND may induce the improved vascularpermeability independent of tumor-induced EPR219.Interestingly, among NDs with different but well definedsurface chemistries, ND-NH2 has induced the highest degree ofvascular leakiness compared to ND-COOH and as-received ND. The proposedmechanism include a ND-triggered cascade of biochemical processes, resulting inopening of tight junctions between the endothelial cells. This effect isreversible and the tight junctions are restored to normal when the ND treatmentceased.

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The observed ND-triggered endothelial tissue leakiness and itsapplication to kill the tumor cells were demonstrated invitro using the Transwell model. When not treated with ND, thevascular barrier well protect the cancer cells in the bottom well fromdoxorubicin (DOX)added to the top well (figures 5(A)–(B)).However, pre-treatment with NDs rendered the vascular barrier transparent toDOX resulting in a significantly higher cancer cell death rate(up to 140%) compared to ?6% death rate observed in the control (notexposed to NDs) vascular barrier model. Dueto its large and fully available surface area (allexternal, 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. Whenentering the cell in the form adsorbed on ND, the drugs cannot be easilyejected by cell efflux mechanisms, instead they areslowly desorbed from ND inside the cell keeping therapeutic concentrations, aneffect that was used to reverse the drug resistance of cancer cells totraditional chemotherapeutics. Therapeutic effluxis the most common mechanism for chemoresistance that limits the effectivenessof cytotoxic drugs. ND-drug complexeshave been shown to bypass the cell protective mechanisms and deliver theanticancer cargo to the cytoplasm through the endosomal release .

The endosomalliberation is triggered by low pH in the endo-some that give the ND surfacechemistry which have been rationally designed that will favor the desorption ofthe drug from ND. Considerably higher IC50 for ND-drug complexes compared tothe drugs alone are associated with sustained release of the drug and are supposedto be beneficial for clinical use, resulting in lower systemic doses andprotecting systemic apoptosis andmyelosuppression caused by cytotoxic therapy221,222. A largesize of ND-drug complex results in a prolonged retention time in a cancer cell.For example, ND-epirubicin complex gives a fluorescencesignal inside LT2-MYC cells after 12 h post-treatment as compared to epirubicinalone or liposomal epirubicin formulation where no fluorescencewas observed after the same period of time. Adsorption on 5 nm ND particles mayalso increase bioavailability of poorly soluble drugs, exposing them to aphysiological environment in the form of a molecule-thick monolayer thefinest dispersion state achieved in principle for poorlysoluble molecules.

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