Nanoparticles (NPs)

• As a platform, nanoparticulates are compatible for developing targeted contrast agents, because:

a)They have a surface, which can be functionalized with one or more targeting molecules at a wide range of densities.

b)Their plasma circulation time can be turned over several orders of magnitude based on their physicochemical properties.

• Advances in nanotechnology may lead to a NP-based tumor-targeting contrast agent that will provide enhanced sensitivity and specificity for tumor imaging enabling earlier detection of metastases

Biological interactions and clearance routes:

• The main parameters governing how NPs interact with biological systems are their size, shape and surface properties.
• It has been found that larger particles experience more rapid clearance than smaller particles.
• NPs with hydrodynamic diameters larger than 200 nm are sequestered by MPS found in the spleen while NPs smaller than 10 nm are usually stealthy to the reticuloendothelial system (RES) organs, these NPs are still found in the liver.
• Majority of clearance for NPs smaller than 5.5 nm are through renal routes thus one must ensure that the NPs are not too small which have a tendency to be removed rapidly by the kidneys.
• In addition to size, surface properties of particles play an important role in RES uptake. It has been found that hydrophilic and neutral surfaces generally are not prone to adsorption or opsonization and are thus more “stealthy” for complement system.
•  
• MRI and CT are the two major technologies currently used for diagnostic imaging.
• 

  Fig 2: Various Contrast Agents

CT

• Over the recent decades, the nanoparticulte contrast agents for CT have been introduced to overcome this limitation. They carry a much higher payload of contrast generating material and increase absorption of X-ray compared to iodine-based contrast agents, meaning that patients can be exposed to lesser doses of X-ray.
• Furthermore, pharmacokinetic properties of these are different to other available agents that may provide imaging over a wide range time window and exhibit better perfusion imaging.
• Various type of NPs have been studied as novel contrast enhancing agents including emulsions, liposomes, micelles, lipoproteins, polymeric NPs and gold NPs for several types of soft tissue.
• In this formulation, the material used to generate contrast is usually encapsulated by NPs. Various compounds can be used for modification and coating of NPs as contrast agents that yield solubility in biological media and biocompatibility

MRI

• The potential types of superparamagnetic particles (SMP) has been evaluated based on size in many preclinical and clinical trials,
• Including:
• (I) micrometer-sized paramagnetic iron oxide (MPIO, micron size),
• (II) superparamagnetic iron oxide (SPIO, nanometeric size) that mainly is used for diagnosis of hepatic diseases and tomur detection and
• (III) ultrasmall superparamagnetic iron oxide (USPIO, <50 nm) that generally are highly useful for blood pool imaging and angiography.
• As compared to Gd, SPIONs show the advantages including tunable size and shape, possibility of surface modification, high sensitivity and effectiveness at low concentrations due to their superparamagnetic property.
• It is clear that it is possible to provide significant enhancment in magnetic resonance activity by proper selection of special coatings on SPIONs

Optical imaging in the second near-infrared (NIR-II) window:

• Optical imaging has advanced rapidly preclinically and holds promise in the clinic owing to the advantages of nonionizing radiation and high spatiotemporal resolution. Advantages are more pronounced in the near-infrared window (NIR), where background is lower and tissue penetration is greater. Compared to the first near-infrared (NIR-I; 700–900 nm) window, the second near-infrared (NIR-II; 1000–1700 nm) window can achieve higher signal-to-noise ratio (SBR) and deeper tissue penetration resulting from lower tissue autofluorescence and lower signal attenuation.
• As such, current optical imaging approaches including FL imaging, PA imaging, self-luminescence are being investigated in the NIR-II window for imaging of tumors lymph nodes and lymphatic vessels specific organs (such as intestines and ovarian) and disease microenvironment.
• 

  Fig 3: Radioactive Contrast Media

• Fluorescence imaging is one of the most convenient and economical imaging modalities. Clinically, it has been used for image-guided surgery with good spatial and temporal resolutions. This noninvasive and nonionizing imaging modality needs relatively low-cost equipment but has fast response times. Du et al. fabricated a NIR-II cyanine dye IR-820 coupled with human serum albumin (HSA) that significantly increased the fluorescence brightness.
  

  Fig 4: The application of IR820-HAS used for NIR-II fluorescence imaging. a) NIR-II fluorescence images of the vasculature at 30 min after intravenous administration of IR820–HSA into C57BL/6 mice (imaging details: 1150 LP, 3000 ms). b-d) NIR-II fluorescence image of Popliteal lymph nodes (white arrowheads), sciatic lymph nodes (blue arrowheads) and connected lymphatic vessels, right inguinal lymph node (green arrowheads) and afferent and efferent lymphatic vessels post injection of IR820–HSA (imaging details: 1000 LP, 1000 ms). e) NIR-II fluorescence images of 143B osteosarcoma tumor-bearing mice at a series of specific time points after IR820–HSA injection (imaging details: 1000 LP, 300 ms). KGaA, Weinheim, Copyright 2019
  

  Fig 5: The application of PTD NPs for NIR-II PA imaging. a, b) Representative two-dimensional ear vasculature imaging of healthy mouse ear (5.00 mm × 5.00 mm, x × y) before (a) and after (b) intravenous injection of PTD NPs. c) 3D ear vasculature image of healthy mouse (5.00 mm × 5.00 mm × 0.54 mm, x × y × z). d, e) Representative two-dimensional imaging of ear of tumor-bearing mouse (7.00 mm × 7.00 mm, x × y) before (d) and after (e) PTD NP injection. f) 3D image ear vasculature of tumor-bearing mouse (7.00 mm × 7.00 mm × 0.76 mm, x × y × z) and white-dashed circle delineated the edges of tumor. KGaA, Weinheim, Copyright 2019