Solid tumors exceeding a certain size rely on a functional blood supply for access to nutrients and oxygen. In contrast to nonmalignant tissues, tumor vasculature often exhibits a leaky appearance, which in principle also allows nanosized particles to reach tumor cells . Being packed into nanoparticles or polyplexes, nucleic acids can be protected from nucleases Inhibitors,research,lifescience,medical which are present in the bloodstream. Nevertheless, systemic delivery of Cyclopamine research buy nanopharmaceutics offers several pitfalls and obstacles, such as aggregation with blood cells, undesired adherence to the vessel wall, or opsonization with
plasma proteins followed by clearance through tissue macrophages (a key component of the reticulo-endothelial system). Inhibitors,research,lifescience,medical Blood proteins interact both with negatively and positively charged nanosystems, whereas a neutral surface charge enables, in principle, blood circulation, as it has been shown for small nanocrystals, so called quantum dots . Alternatively, nanosystems can be decorated with hydrophilic polymers, which, owing to their Inhibitors,research,lifescience,medical excessive hydration, shield the particles’ surface charge, hereby preventing the aggregation with protein components. From the group of hydrophilic polymers, like N-(2-hydroxypropyl)methacrylamide
(HPMA) , hydroxyethyl starch (HES) , or polyethyleneglycol (PEG) , PEG is the most commonly used one. In addition, targeting entities can be used to direct the nanocarrier to specific cells. Commonly, these are ligands that bind to receptors, or other cell surface molecules, that are overexpressed Inhibitors,research,lifescience,medical in tumor cells. Macromolecular drugs, which exceed the renal excretion limit and are able to circulate in the Inhibitors,research,lifescience,medical blood stream, can benefit from the so-called enhanced permeability and retention (EPR) effect: nanopharmaceutics
accumulate in tumor tissue as they can penetrate the leaky vasculature but are retained within the tumor tissue due to incomplete lymphatic drainage ADAMTS5 . This tumor deposition is a prerequisite for all steps that follow: binding to and internalization of the particles into target cells. The latter can be promoted by the incorporation of the earlier mentioned cell-binding ligands into the carrier system. Figure 2 summarizes the limitations in nucleic acids delivery, the solutions for such limitations, and the therapeutic advantages of nucleic acid nanosystems. Figure 2 Advantages and limitations in nucleic acid nanosystems delivery. Particular advantages of nucleic acid therapies are (1) the ability to include tissue specific targeting (or transcriptional targeting) and (2) the possibility to systemically deliver genes … 5.