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Article

Clearance pathways of near-infrared-II contrast agents


Review

. 2022 Nov 14;12(18):7853-7883.


doi: 10.7150/thno.79209.


eCollection 2022.

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Review

Sha Yang et al.


Theranostics.


.

Abstract

Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications. The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility. Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging. Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention. In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed. The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted. Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents.


Keywords:

biocompatibility; hepatobiliary clearance; in vivo imaging; near-infrared-II; renal clearance.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures



Figure 1

Clearance pathways of NIR-II contrast agents.


Figure 2


Figure 2

Clearance pathways of contrast agents. Contrast agents are cleared through the kidney, liver, and MPS pathways. Solid arrows represent the most probable interaction, and dashed arrows mean possible interaction. If the contrast agents with HD < 6 nm or MW < 40 kDa, they can be cleared by renal clearance within minutes to hours after administration. If the contrast agents with HD >8 nm or MW > 40 kDa, they can be cleared by hepatobiliary clearance within hours to days after administration. Non-degradable or larger-sized matters are more likely to be internalized and retained by MPS. If MPS degrades the contrast agents, their decomposer may avoid sequestration and return to the blood circulation for eventual renal or hepatobiliary clearance. Notably, MPS includes the Kupffer cells in the liver.


Figure 3


Figure 3

Transport of contrast agents with different sizes and surface charges in the urinary system (reproduced from ref. with permission from Springer Nature and ref. with permission from Elsevier).


Figure 4


Figure 4

Transport of contrast agents in hepatobiliary system and MPS. (A) Schematic illustration of the hepatobiliary processing and clearance of contrast agents: (1) enter into the liver via the portal vein, (2) matters across the hepatic sinusoid, (3) be likely to accumulate in Kupffer cells, (4) probably leak into the space of Disse and be endocytosed by hepatocytes, (5) transcytose via the hepatocytes and enter into the bile duct via bile canaliculi, (6) go through the hepatic ducts, (7) Contrast agents may first collect in the gall bladder, (8) Contrast agents may enter into the common bile duct, (9) Contrast agents may be cleared into the duodenum of the small intestines via the sphincter of Oddi, (10) eventually cross the entire gastrointestinal tract and are cleared in feces (reproduced from ref. with permission from Elsevier). (B) Different biliary elimination processes of colloids by hepatocytes: (1) fluid-phase endocytosis (pinocytosis), (2) direct receptor-mediated transcytosis, and (3) receptor-mediated transcytosis followed by passage through lysosomes. The shock symbol denotes acidic and oxidative conditions (reproduced from ref. with permission from Elsevier). (C) Contrast agents that are not toxic to the cell function or mobility can be effectively uptaken by circulating blood-borne monocyte-macrophages and then transported to the areas of the lymphoid and MPS (for example, liver and spleen). (D) Scheme of strategies to prevent contrast agents uptake by MPS, especially Kupffer cells (reproduced from ref. with permission from Elsevier).


Figure 5


Figure 5

Clearance of SWNTs. (A) Structure of single-walled carbon nanotubes (reproduced from ref. with permission from Wiley-VCH Verlag GmbH. (B) SWNTs fluorescence images of the cerebrovasculature of the mice without craniotomy in the NIR-I, NIR-II, and NIR-IIb regions and with the corresponding signal-to-background (SBR) analysis. (C) The half-life of SWNTs blood circulation. (D) The semiconducting LV SWNTs accumulation in the liver (11% ID/gram) and spleen (14% ID/gram) of MPS (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 6


Figure 6

Clearance of 6PEG-Ag2S QDs. (A) Scheme of the 6PEG-Ag2S QDs with emission at 1200 nm upon 808 nm excitation. (B) NIR-II fluorescence imaging of 6PEG-Ag2S QDs in a xenograft 4T1 tumor-bearing mice. (C) The tumor-to-background ratio (TBR) plotted as a function of time p.i. for the NIR-II images, the representative plot of the %ID/gram of the 6PEG-Ag2S QDs in the blood after tail-vein injection, and the quantitative biodistribution of 6PEG-Ag2S QDs in various organs and tumor at 72hours p.i. (D) Short-term retention and clearance study of 6PEG-Ag2S QDs measured by ICP-MS. (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 7


Figure 7

Clearance of Ag2Se QDs. (A) Scheme showing the preparation process of clearable ultrasmall Ag2Se QDs. (B) In vivo fluorescence imaging of Ag2Se QDs-PEG in nude mice within 6 hours after intravenous injection. (C) Ex vivo fluorescence images of Ag2Se QDs-PEG in tissues after intravenous injection and the distribution of Ag2Se QDs-PEG in mice based on tissue fluorescence intensity (% ID). (D) Clearance of Ag2Se QDs-PEG from mice (reproduced from ref. with permission from American Chemical Society).


Figure 8


Figure 8

Clearance of rare earth materials. (A) Scheme of the hydrophilic ErNPs with crosslinking polymeric layers and amine groups on the surface as conjugation sites. (B) The clearance of ErNPs from the liver and spleen via plotting the signal intensity within two weeks. (C). Biodistribution of ErNPs in main organs and feces of ErNPs-treated mice at 14 days p.i. (reproduced from ref. with permission from Springer Nature). (D) Schematic structure of RENPs@Lips. (E) Selected time points of in vivo NIR-II imaging from the whole-body and representative feces samples after intravenous injection of Rare earth contrast agents@Lips. (F) Quantitative analysis of NIR-II fluorescence intensity in vivo (liver and spleen region) (reproduced from ref. with permission from Wiley-VCH Verlag GmbH). (G) Scheme of the NIR-II bioimaging for the acute local epidermal inflammation in the mice after intravenous injection of the ultra-small DCNP@GSH nanoprobes. (H) DLS results of DCNP@GSH and DCNP@OH in H2O2-containing mouse serum. (I) Pharmacokinetics of DCNP@GSH in the blood and urine clearance after intravenous administration. (J) Clearance of DCNP@GSH and DCNP@OH in urine and feces (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 9


Figure 9

Clearance of Ir-B-TiO2@CCM. (A) The synthesis and mechanism of action of Ir-B-TiO2@CCM for multifunctional theranostic NIR-II photothermal/sonodynamic imaging and therapy. (B) Biodistribution after intravenous injection of Ir-B-TiO2@CCM for various time intervals (from 2 hours to 48 hours) is determined as the amount of titanium per gram of tissue by ICP-MS. (C) Blood-circulation time after intravenous injection of B-TiO2, Ir-B-TiO2, or Ir-B-TiO2@CCM (reproduced from ref. with permission from Elsevier).


Figure 10


Figure 10

Clearance of other NIR-II inorganic contrast agents. (A) The stepwise synthesis of liquid metal@SiO2-RGD targeted core/shell nanoparticles, detailed composition/nanostructure, unique functionality for tumor-targeted accumulation, and subsequent photothermal tumor hyperthermia in the NIR-II window. (B) In vivo biodistribution of Ga in major organs and tumors as well as accumulated Ga in feces and urine cleared out of the mice body (reproduced from ref. with permission from American Chemical Society). (C) The crystal structure of gold clusters has 25 gold atoms as the core and 18 sulfur atoms. (D) Size of gold clusters detected with TEM. (E) Photoluminescence (PL) versus excitation spectra of gold clusters with an emission center of 1120 nm. (F) Blood half-time of gold clusters determined by ICP-MS. (G) ICP-MS measurement of the time-dependent concentration of gold clusters in urine and feces. (H) Cumulated urine, feces, and total (urine and feces) clearance of gold clusters with collected time within 48 hours (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 11


Figure 11

Clearance of NIR-II contrast agents based on conjugated polymers. (A) Schematic illumination for PDFT1032 nanoparticle consisted of semiconducting polymer DFT and a hydrophilic DSPEm-PEG shell. (B) The ex vivo biodistribution for different organs (reproduced from ref. with permission from Royal Society of Chemistry). (C) Chemical structures of the conjugated polymer, the purple region represents the quinoid polymer backbones, and the blue region represents the electron-withdrawing group. (D) Ex vivo NIR-II imaging of the vital organs (heart, liver, spleen, lung and kidney) (reproduced from ref. with permission from American Chemical Society). (E) Chemical structural formula of the semiconducting polymer DPP-BTzTD, functional polymer PSMA, and Triton X-100. (F) NIR-II fluorescence imaging of various organs dissected from mice after the intravenous injection of S-Pdots at different time points p.i. (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 12


Figure 12

Clearance of NIR-II molecular contrast agents encapsulated in amphiphilic matrixes. (A) Schematic illumination of the p-FE synthesis, chemical structures of FE, and the PS-g-PEG polymer. (B) High-magnification of NIR-II fluorescence imaging of a 4T1 tumor in a mouse with two colors. (C) The clearance behavior of p-FE (reproduced from ref. with permission from Springer Nature). (D) Schematic illustration of DTTB@PEG NMs preparation. (E) NIR-II fluorescence images of the 4T1 tumor-bearing mice obtained at different times p.i. (F) Semiquantitative analysis of the NIR-II fluorescence signals in 4T1 tumor regions at different times. (G) Biodistributions of DTTB@PEG NMs at 36 hours p.i. (reproduced from ref. with permission from American Chemical Society). (H) Scheme of the synthesis and chemical structures of BPN-BBTD NPs. (I) Absorption and PL spectra of BPN-BBTD in chloroform. (J) Biodistribution of BPN-BBTD NPs in various organs of subcutaneous (up) and orthotopic tumor-bearing mice (down) (reproduced from ref. with permission from American Chemical Society).


Figure 13


Figure 13

Clearance of NIR-II contrast agents encapsulated in or modified with proteins. (A) Schematic drawing of the interaction of IR820 with HSA. (B) NIR-II fluorescent image of IR820, IR820-HSA, and IR820-HSA heated at 60 °C. (C) The distribution of IR820-HSA in the major organs and tumors dissected from mice at 8 hours. (D) Semiquantitative analysis of fluorescence intensity of IR820-HSA imaging in different organs of 143B tumor-bearing mice (reproduced from ref. with permission from Wiley-VCH Verlag GmbH). (E) Synthesis of H2a-4T@Cetuximab complex and the NIR-II fluorescence imaging and phototherapy. (F) Ex vivo fluorescence images of H2a-4T@Cetuximab in the main organs and tumors of HCT116 tumor-bearing mice at 24 hours. (G) Quantitative analysis of mean fluorescence intensity in different images of organs and tumors (reproduced from ref. with permission from Wiley-VCH Verlag GmbH). (H) Schematic illumination of the combination of PD-L1 mAb and IR-BGP6. (I) Comparison of anti-PD-L1-BGP6 and IR-BGP6 for targeting the PD-L1 positive cancer cell line MC38 in vitro. (J) Clearance behaviors of the NIR-II fluorescence probe IR-BGP6 (reproduced from ref. with permission from Wiley-VCH Verlag GmbH).


Figure 14


Figure 14

Clearance of NIR-II contrast agents modified with water-soluble polymers. (A) Chemical structure and synthesis of CH1055 and CH1055-PEG. (B) PL excitation spectra of CH1055-PEG. (C) Selected time points of CH1055-PEG from NIR-II imaging in a mouse with the supine position. (D) The representative fluorescent signal intensity of CH1055-PEG in both the liver and bladder regions (reproduced from ref. with permission from Springer Nature). (E) Synthetic route of FBP 912. (F) In vivo bioimaging of FBP 912 in Balb/c mice with the dorsal or ventral position. (G) The ratios of bladder-to-liver intensity and renal clearance efficiency (RCE) as a function of time p.i. of FBP 912 in living mice (reproduced from ref. with permission from Wiley-VCH Verlag GmbH). (H) Design the bright renal-clearance contrast agent IR-BEMC6P with shielding and donor group optimizations. (I) NIR-II imaging of the IR-BEMC6P in the mouse indicated high fluorescence signals in the bladder at different time points after intravenous injection (reproduced from ref. with permission from Royal Society of Chemistry).


Figure 15


Figure 15

Clearance of a NIR-II contrast agent modified by ammonium ionization. (A) The structure and application of SWIR-WAZABY-01. (B) Absorption and PL emission range of SWIR-WAZABY-01. (C) The distributions were observed from 24 to 168 hours p.i. (reproduced from ref. with permission from American Chemical Society).


Figure 16


Figure 16

Clearance of NIR-II contrast agents modified by sulfonic ionization. (A) Synthetic route of LZ-1105. (B) Normalized absorption and fluorescence intensity of LZ-1105 in PBS. (C) NIR-II bioimaging in vivo. (D) Cumulative urine clearance curve of LZ-1105 in mice within 24 hours p.i. (reproduced from ref. [138]with permission from Springer Nature).


Figure 17


Figure 17

Clearance of RENPs-based water-soluble metallo-organic compound. (A) Schematic structure illustration of the DTPA and Nd-DTPA, along with the synthesis process of Nd-DTPA and bioapplication process in the NIR-II window under the 808 nm excitation. (B) In vivo NIR-II imaging of kidney signals of a mouse in the supine position (reproduced from ref. with permission from Elsevier). (C). Chemical structure and the one-step synthesis of Nd-DOTA. (D) Absorbance and stimulated emission spectra of Nd-DOTA. (E). Selected time points from video-rate NIR-II imaging (850 nm and 1000 nm long-pass filter for ICG and Nd-DOTA, respectively) of a mouse in the supine position after an intravenous injection of Nd-DOTA (top) and ICG (down) showing disparate liver and bladder fluorescent signals (n= 3 mice) (F) Cumulative urine clearance curve of Nd-DOTA (% ID) as well as blood circulation (% ID/g) time points fitted with an exponential decay obtained during the 9 hours p.i. (reproduced from ref. with permission from American Chemical Society).

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