Introduction to Nanomedicine.

Although mentions of nanoparticles in relation to biomedicine appeared in the late 1970s and are now the subject of over 10,000 publications per year, the term “Nanomedicine” only appeared at the turn of this century, and less than 30 papers including this term were published up to 2005. Ten years later, Web of Science indicates the publication of more than 1000 Nanomedicine articles in 2015 among more than ten times more articles involving nanoparticles for biomedical usage. Nanomedicine has been defined by the European Science Fundation’s forward Look Nanomedicine as follows: “Nanomedicine uses nano-sized tools for the diagnosis, prevention and treatment of disease and to gain increased understanding of the complex underlying patho-physiology of disease. The ultimate goal is to improve quality of life.” [1]. It involves the three nanotechnology areas of diagnosis, imaging agents and drug delivery with nanoparticles in the 1–1000 nm range, bioships (from both “top-down” and “bottom-up” sources) and polymer therapeutics [2,3]. A relevant more recent terminology is that of “theranostics” [4,5] involving both diagnostics and therapy with the same nanopharmaceutics. In fact, Nanomedicine can be traced back to the use of colloidal gold in ancient times [6,7], but Metchnikov and Ehrlich (Nobel Prize for Medicine in 1908) are the modern pioneers of nanomedicine for their works on phagocytosis [8] resp. cell-specific diagnostic and therapy [9]. Seminal works on nanoparticles for nanomedicine were increasingly developed in the last 30 years of the 20th century and included liposomes [10,11], DNA-drug complexes [12], polymer-drug conjugates [13], antibody-drug conjugates [14], polymer nanocapsules [15–17], polymer-protein conjugates [18], albumin-drug conjugates [19], block-copolymer micelles [20], anti-arthritis gold nanoparticles [21] and anti-microbial silver nanoparticles [22]. These nanomedicines have various size ranges that are often not strictly within the standard definition of the nanoworld that is 1–100 nm [23]. Clinical toxicities including side effects have been broadly studied and sometimes point toward patient individualization. Problems that need be overcome are that most drugs are neither specific nor water-soluble. The above nanocarriers have been designed to first solubilize drugs in aqueous media, then serve as nanovectors toward specific targets and control drug release. A majority of nanocarriers used now allow oral drug delivery. Although these nanovectors are designed to translocate across the gastro-intestinal tract, lung, and blood-brain barriers, the amount of drug transferred to the organ is lower than 1%, therefore improvements are challenging [24,25]. Nanovector-drug assemblies are designed to maximize the benefit/risk ratio, and their toxicity must be evaluated not only by sufficiently long term in vitro and in vivo studies, but also pass multiple clinical studies. For biological assays, these nanomaterials must be characterized very strictly in a fully reproducible way [26,27]. Suitable nanocarriers (including metabolites) must be subjected to research of their antigenicity, immunotoxicity and possible activation of complements (that are a group of serum proteins that activates inflammation, destroys cells and participates in opsonization), pharmacokinetics, biodistribution, and drug release rates [28]. Tumor targeting drugs are a major focus in this context, and they use liposomes, polymers, micelles, conjugates, nanoparticles and conjugates of these nanopharmaceutics [29]. Two main routes are passive targeting using the enhanced permeation and retention (EPR) effect [30,31] and active targeting involving covalent drug attachment using linkers to a receptor that should be specifically recognized by the cancer cells [32]. Drug release rates and stability until the targeted cells are