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. 2012 Dec;2(4):266–273. doi: 10.3978/j.issn.2223-4292.2012.12.04

Table 1. 4S design considerations for targeted contrast agents.

4S criteria determining properties Definition, considerations, and requirements
Stability: physicochemical, optical, and biological properties Ability to resist changes in chemical, physical, and optical properties in biological and physiological conditions over time
Determinable factor for solubility, aggregation, degradation, serum protein binding, and nonspecific uptake in vivo
Physicochemical stability (solubility) is governed by chemical composition, HD, hydrophilicity/lipophilicity, and surface charge
Optical stability: photobleaching, photodegradation, and quenching
Sensitivity: detectability and optical properties Ability to detect either the probe signal at the target (direct response) or change in a signal, depending on the quantity of probes at the target (indirect response)
Maximum excitation and emission wavelength in the NIR range for deep tissue imaging
Require high extinction coefficient and high quantum yield
Specificity: targeting properties (Organ vs. Cellular) Ability to distinguish the target from non-target processes or tissues (enhanced contrast)
Require high concentration of contrast agents per unit volume of target tissue: targeting improves image resolution by enhancing the target signal and reducing background signals.
Organ-specific targeting (mode of action): effective delivery to the target tissue (i.e., biodistribution, pharmacokinetics, and clearance)
Cellular-specific targeting (mechanism of action): active and activatable targeting
Safety: physicochemical, biological, and physiological properties Ability to resist innate immune defenses or undesirable consequences related to toxicity
Affecting factors are molecule’s size, surface chemistry, formulation, surface physics, dosage and route of administration, and ADME (absorption, distribution, metabolism, elimination).
Require nontoxic, biocompatible, or biodegradable properties