**Acknowledgements**

accumulation of AuNPs in mice showing that most of the intravenously injected nanoparticles are retained in the liver, regardless of their size [156-158]. There is also an agreement in that AuNPs have the ability to transpose the blood-brain barrier and thus reach the brain, with a cut-off limit in diameter of around 20 nm [159], and that smaller particles have the most widespread organ distribution [156-158]. Organ distribution seems to be ruled by a more or less complex relationship with nanoparticle size. For instance, it is known that renal excretion of AuNPs is maximized for a narrow size range of 6-8 nm, resulting in an accelerated clearance rate [160]. Despite the valuable use of animal models, the effect of size on the toxicity of AuNPs in humans is difficult to predict since the size of endothelial cells' fenestrae is highly variable between individuals, thereby affecting nanoparticle clearance [75]. Therefore, more consistent data on the toxicological profile of AuNPs in vivo is necessary. For a more complete review on biodistribution, encompassing earlier studies and administration routes other than intravenous injection, see Khlebtsov and Dykman [159]. Furthermore, core size, charge and surface chemistry of AuNPs seems to correlate to toxicity on the development of zebrafish embryos, with positive and negatively charged AuNPs causing mortality and malfunctions to the embryos, respectively [161]. Adverse effects were also found in the model system Droso‐ phila melanogaster after exposure to citrate-capped AuNPs, which were shown to reduce

Nonetheless, long-term studies in higher organisms are necessary to further characterise the safety of AuNPs as therapeutic agents, so they can be safely administrated to humans without

Cancer is a complex disease with a plethora of cell types and differentiation stages that trigger standard molecular mechanisms towards recruitment of cells and nutrients to enhance survival and proliferation. Cancer complexity is also dependent from the specific and multi‐ faceted umor microenvironment. All these different molecular pathways, mechanism and markers can be used as potential targets for therapeutics. However, current therapeutics (drugs and molecules) show serious cell toxicity that is not merely directed at the cancer cells but instead promote off-target cellular disarray and cell death, usually reported ad undesirable

Nanomedicine has been putting forward several therapeutic concepts that disrupt the way we have been dealing with cancer therapy, i.e. nanoparticles as drug delivery agents, minimising side effects and toxicity of the drugs. Furthermore, these nanoparticle platforms allow for selective targeting of cancer cells or tumor vessels either by incorporating novel or standard anticancer drugs and/or the delivery of therapeutic genetic modulators. These approaches, often based on the robustness and chemical properties of AuNPs, have shown great promise in preclinical models. Some recent advances in ligand-targeted NPs have begun to demonstrate

fertility in a dose-dependent manner and also the life span [144, 162].

concerns about late toxicity symptoms.

140 Application of Nanotechnology in Drug Delivery

**5. Conclusions & future**

side effects and systemic toxicity.

improvement in cancer therapy.

The authors acknowledge Fundação para a Ciência e Tecnologia (FCT/MEC) for funding: CIGMH (PEst-OE/SAU/UI0009/2011); PTDC/BBB-NAN/1812/2012.
