Explanation:
Systemic Circulation
Related terms:
ChitosanDrug Micelle
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Nanoscale Drug-Delivery Systems
Anthony Singer, ... Shyam S. Mohapatra, in Nanocarriers for Drug Delivery, 2019
5.2 Challenges of Systemic Circulation and Cellular Internalization
In systemic circulation there is a danger of fouling, which is essentially the loss of function of NPs due to degradation, alteration, or mild to severe denaturation due to natural internal interactions during administration [60]. This must be accounted for in the design of the nanoformulation by conjugation of antifouling (stabilizing) agents that will maximize the stability and protection of its conjugate. In addition, any specific barriers encountered during administration must be taken into consideration by employing a mechanism to overcome the barrier. Stabilizing agents also aid in extending the half-life, maximizing delivery to the target site, preventing nonspecific premature drug release or nonspecific cellular uptake, and overall eliminating cytotoxic effects. Targeting also enhances specific delivery. Another challenge of free NPs in the systemic circulation is the prevention of opsonization, which signals for degradation and clearance from the bloodstream. This can be prevented by conjugating specific polymers, such as PEG. Size also plays a role in whether the NP is detected. Last, any NP that enters the human body and is immersed in body fluids can become coated by natural body proteins forming a protein corona [60]. In response, the NP's in vivo physicochemical interaction can be inhibited or altered to the point that its therapeutic function is lost. For example, a natural protein can successfully compete for a targeting moiety and prevent the intended ligand–receptor interaction. However, the protein corona can be controlled by functionalization to inhibit its formation or bond specific types of proteins that could aid in delivery or protection [60].
If there are no extracellular release stimuli when a target cell is reached, the intracellular delivery for an NP highly depends on its ability to survive cell entry, or internalization. This process typically relies on a phagocytic path of entry, which exposes the NP to acidic environments and also requires endosomal vacuole escape [53]. Other paths may include entry through pores in the cell membrane or facilitation by transmembrane proteins. If release is not intended to be cytoplasmic, then conjugates to aid in intracellular trafficking must be employed to cause organelle-specific drug delivery [54]. Mitochondria and the nucleus of a cell are often targeted organelles, but both have membranous barriers that must be overcome.
Most importantly, nanotherapeutics must be safe. Primarily, the body's cytotoxic response is evaluated, but on top of what has been mentioned in the last paragraphs about stable targeting, the components of the nanotherapeutic must be biodegradable. This means that any unused component, such as the nanocarrier and its conjugates, can be safely broken down and excreted from the body without induction of a cytotoxic effect. In addition, the utilization of biocompatible components (those that are either found naturally in the body or can be naturally metabolized or defended against) severely reduces cytotoxicity [14].
