All NPs contain at least two fundamental spatial components: the core and the corona that interact with the environment or solvent. While core/shell, core/multishell systems add further complexity, for example [18
], all still possess an area in which NP interfaces with the solvent (). PEG chains modify this interface layer and increase circulation time. Circulation half-time (t½
) describes blood pool residence and is the period over which the concentration of circulating NPs remains above 50% of the injected dose, analogous to a drug's half-life [19
]. NP efficacy requires sufficient t½
to not only reach the target, but also remain in the affected area (at concentrations sufficiently above background tissue) long enough for image capture or drug delivery. The RES system prevents site-specific accumulation because it removes the NPs from circulation, acting as a competitor to the intended target site [20
]. In addition, the NPs must clear from the non-targeted area to produce imaging contrast or dosing efficiency.
The ideal t½ is dependent on application. In imaging, 2–6 h is optimal for injection, accumulation at targeted site, clearance from nontargeted areas and data collection. The ideal circulation time for therapeutic NPs is longer (days) to allow repeated exposure to affected area. Unfortunately, this can also expose healthy organ systems to the drug and is the motivation for targeted NPs, as such systems preferentially accumulate in the diseased area.
Approaches to measuring t½
vary with NP type. When labeled with radionuclides, γ counting of either specific organ systems or blood aliquots determines NP circulation time. One limitation is dissociation of radionuclide from NPs; however, radioactivity measurements may always be carried out noninvasively [21
]. Measurement of t½
via fluorescence, Raman, inductively coupled plasma or chromatography/mass spectrometry is very specific to the NP, but requires sequential sampling of the blood pool.
The RES is an immune system component, utilizing circulating macrophages and monocytes, liver Kupffer cells and spleen and other lymphatic vessels to remove foreign material, such as bacteria and viruses, from the body [20
]. illustrates how opsonin proteins associate with foreign bodies and coat its surface [22
]. As bacteria and viruses have the same negative surface charge as phagocytic cells, opsonins are critical to reducing the charge repulsion between the two systems [13
]. Next, phagocytic cells engulf the material and transport it to the liver or spleen for degradation and excretion (). Additional phagocytic macrophages are permanently located in the liver. Known as Kupffer cells, these cells serve as a major filter for many types of NPs and are a major interference with long t½
]. The PEG polymer on a NP surface increases t½
by reducing this opsonization process (), thus preventing recognition by monocytes and macrophages, allowing the NPs to remain in the blood pool [13
]. Hydrophobic particles are also more vulnerable to the RES and hydrophilic PEG reduces these complications [22
Polyethylene glycol prevents uptake by the reticuloendothelial system
In addition to NP–RES interactions, poor t½
can also result from NP–NP interactions (i.e., aggregation). NPs aggregate primarily because the attraction between particles is stronger than the attraction for solvent [13
]. NPs with a high surface energy have a greater tendency to aggregate as described by the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory [25
]. For spherical NPs, the interaction potential is related to the electrostatic repulsive potential and the van der Waals attraction potential [26
]. PEG decreases the surface energy of NPs and minimizes van der Waals attraction [27
Aggregation can be induced by solvents of high (>100 mM) ionic strength (shielding of solvent from NP), highly concentrated solutions of NPs (less distance between the NPs), time from synthesis, or NP preparations with a very neutral (~±5 mV) zeta potential [30
]. PEG decreases the amount of attraction between NPs by increasing the steric distance between them and increasing hydrophilicity via ether repeats forming hydrogen bonds with solvent. Other benefits to PEGylation include modifying the size of the particle. The reduced renal filtration of particles larger than 10 nm increases t½
; however, at too large a size (>100 nm), liver uptake increases and EPR extravasation may decrease [31
]. PEG modifies the NP flexibility and the NP can become `softer' after PEGylation than the underlying material, influencing extravasation.