TABLE 3.

Summary of Studies Reporting the Biological Fate of QDs

Quantum dot composition and (emitting wavelength)	Hydrodynamic diameter	Route of administration and (model organism)	Duration of exposure (and dose, if reported)	Fate of QD	Observations of in vivo toxicity	Reference
CdSeS/silica-hydroxyl (maximal emission at 570 nm)	21.3 ± 2.0 nm	Intravenous injection (male mice)	0–5 days (5 nmol per mouse)	- The plasma half-life of QD was 19.8 ± 3.2 h.	Authors noted a lack of toxic effects during the 5-day course of their experiment, but acknowledged that the long-term stability of the CdSeS/SiO2 QDs in vivo remained an unknown factor and that this is an area that will require further study.	(Chen et al., 2008)
				- The clearance of QD was assessed at 57.3 ± 9.2 ml/h/kg.
				- The liver and kidney were the main target organs for QD, but there accumulation was also noted in spleen and lung. The peak concentration of QD accumulation occurred 6-h postinjection (peak was 12 h in the lung).
				- In this study, a fraction of free QD was excreted via urine as small molecules within 5 days.
				- The majority of QDs bound to protein and aggregated into larger particles; these were metabolized in the liver and excreted via feces.
				- QDs in the spleen, lung, and kidney were thoroughly eliminated within 48 h.
				- After 5 days, 8.6% of the injected dose of aggregated QDs remained in the liver; it was difficult for this fraction to clear, indicating that clearance of QDs was incomplete.
				- By 1-h postinjection, the QD were mostly cleared from the circulation.
				- At the 1-h time point, QD conjugated to a lung-specific mAb accumulated primarily in the lung. QD not targeted to the lung accumulated primarily in the liver and spleen.
				- By 24 h, lung-targeted QD had redistributed to liver and spleen, suggesting that they were being taken up by cells of the RE system. There was also an increase in radioactivity in the kidney, indicating excretion.
				- Temporary inhibition of the RE system demonstrated involvement of RE cells in clearance of QD from lungs and redistribution to liver and spleen.
CdTe/ZnS-mAb (monoclonal antibody (mAb) targeted to lung).	Not reported	Intravenous injection (female mice)	1 h, 24 h, 7 days, 19 days	- Long whole-body QD retention times were observed (> 2 weeks).	In this study, it was not possible to distinguish between any possible toxic effects of the QD themselves versus toxicity of the radiolabel, therefore no conclusions could be drawn regarding QD toxicity.	(Kennel et al., 2008)
*Radiolabeled with Te-125m
CdSeTe/ZnS-methoxy-PEG5000 (705 nm)	18.5 nm	Intravenous injection—tail vein (mice)	0–24 h, 1–28 days, and 6-month time points (40 pmol)	No significant excretion or metabolism of QDs was observed in the 28 days following dosing. QD were concentrated in the spleen, liver and kidneys.	Renal tissues, examined at 6 months by TEM, showed proximal tubular degeneration, indicating possible toxicity. Changes in mitochondria were particularly evident.	(Lin et al., 2008)
CdSe/ZnS	16 nm	Injected subcutaneously—right anterior paw (mice)	0–24 h	QD detected in lymph nodes within minutes (∼2.42% of total dose). Did not detect QD migration to liver, kidneys or spleen. Authors also found no evidence of QD excretion. Peak QD concentration in lymph nodes detected at 60 min; fourfold decrease seen by 24 h.	Toxicity was not assessed in this study.	(Robe et al., 2008)
CdSe/ZnS-Cys size series (515–574 nm).	4.36–8.65 nm	Intravenous injection (rats and mice)	0–4 h (100 μl of 3μM 99mTc-QD in mice; in rats 10 pmol/g animal weight)	- Radiolabeled QD with diameters of 4.36, 4.99, and 5.52 nm were found to be excreted into the bladder within 4 h.	Toxicity was not assessed in this study—authors argue that in vivo toxicity is less of an issue if QD are excreted.	(Choi et al., 2007)
*Zwitterionic surface charge (Cys) found to prevent serum protein absorption; this produced the highest solubility and smallest possible diameter.
				- QD larger than 5.6 nm were never excreted, but instead were found to be trapped in the liver, lung, and spleen.
				- The blood half-life of QD ranged from 48 min to 20 h, as the diameter of QD increased from 4.36 to 8.65 nm.
CdSe/ZnS-PEG (655 nm); and CdSeTe/ZnS-PEG (800 nm)	22.6, 30.4, and 41.2 nm	Injection into human and mouse tumor models (mice)	0–90 min. Animals kept for up to 2 years (5–25 μl of a preparation containing 25–100 pmol QD)	Injection of QD into tumors yielded rapid migration (within minutes) into adjacent sentinel lymph nodes.	Authors state that the toxicity of amp-coated CdSe/ZnS QD was minimal or nonexistent for over 2 years, as assessed by pathological examination of animals.	(Ballou et al., 2007)
CdSe/CdS-PEG (621 nm)	37 nm	Intradermal injection—right dorsal flank (mice)	0–24 h	Majority of QD remained at site of injection. Detected QD in regional lymph nodes within minutes. At 12–24 h, detected QD primarily in the liver (∼6% of total dose), lymph nodes (∼1%) and kidneys (∼0.5%). Also detected QD in spleen, hepatic lymph node and heart (heart may have been an artefact due to method of animal sacrifice).	Toxicity was not assessed in this study.	(Gopee et al., 2007)
CdTe/ZnS-PEG (commercially available QD705)	13 nm	Intravenous injection via tail veins (mice)	Up to 28 days: 1, 4, 24 h, 3, 7, 14, and 28 days (40 pmol per mouse)	- Plasma kinetics revealed a clearance rate from the blood of 2.3 ml/h/kg. The plasma half-life was calculated at 18.5 h.	- Tissues were subject to pathological examination. This analysis revealed marked sinusoidal congestion and increased multinucleated giant cells in vascular areas of the spleen. Notably, liver and kidneys displayed no remarkable abnormalities.	(Yang et al., 2007)
				- QD persisted in spleen, liver, and kidneys throughout the experimental period (up to 28 days). QD levels in liver and kidneys increased over time.
				- QD were not detectable in feces and were present only at low levels in urine, indicating that essentially no excretion occurred in 28 days.
CdTe/ZnS-DOTA ± peptide (commercially available QD705)	∼20 nm	Intravenous injection (tumor-bearing mice)	1-, 5-, 18-, and 25-h time points (20 pmol per mouse)	- Peptide conjugated QD were specifically targeted to tumors.	Toxicity was not assessed in this study.	(Cai et al., 2007)
				- For both peptide conjugated and unconjugated QD, a majority of the QD were found to localize to liver (100:1), spleen (40:1) and bone marrow (ratios represent tissue-to-muscle ratios). To a lesser extent, QD also localized to the kidneys (1:1 ratio) and lymph nodes.
CdSe/ZnS ± PEG (commercially available QD525 and QD800)	21 and 12 nm	Intravenous injection (mice)	0–15 min following injection, then 1.0, 4.5, 12, and 36 h (25 pmol per mouse)	- The circulation time of PEG-coated QD was 6 min (vs. 2 min for uncoated QD).	- Authors comment that no evidence of acute toxicity was observed during and following the experimental period. Authors also comment that their data “suggest” that the QD exhibited good stability in vivo, though they acknowledge that no formal serum stability studies were performed.	(Schipper et al., 2007)
				- The major organ of uptake of QD was liver; QD also found in spleen.
				- Localization of QD to liver and spleen was almost immediate (within 2 min).
				- Found that the size of the QD had no effect on biodistribution, within the size range tested in this study.
				- Authors found no evidence of clearance of QD from mice.
				- PEG-coated QD also showed low-level uptake to bone.
CdTe/ZnS-mAb targeted to lung	Diameter not reported: molecular weight was 1–5 × 106 Da	Intravenous injection (mice)	0–144 h	- QD bound to a lung-specific monoclonal antibody (mAb) were effectively targeted to the lung and remained in lung for up to 6 days.	Toxicity was not formally assessed in this study, but authors noted that no acute toxicity was observed.	(Woodward et al., 2007)
				- QDs bound to a control mAb were found to migrate primarily to the spleen, liver, and kidneys.
				- Authors observed that QD were cleared from the body to a limited extent, but that clearance was slow.
CdSe/ZnS-LM, CdSe/ZnS-BSA	25, 80 nm	Intravenous injection (male Sprague-Dawley rats)	10 days (5 nmol dose per rat)	- QD half-lives were etermined to be 39–59 min; QD were cleared from the plasma between 0.59 and 1.23 ml/min/kg.	Toxicity was not assessed in this study.	(Fischer et al., 2006)
				- By 90 min, approx. 90% of the BSA-coated QD were found in the liver; other tissues (spleen, lymph nodes, bone marrow) also retained small amounts.
				- There were distinct differences between the plasma clearance and tissue distribution of uncoated and BSA-coated QD.
				- Authors could not detect QD in either feces or urine, and therefore concluded that the QD were not excreted.
InAs/ZnSe-DHLA-PEG	8.7 nm	Injected both subcutaneously and intravenously (in both mice and rats)	Approximately 5 min	- QD were specifically engineered to have small diameters.	Toxicity was not assessed in this study.	(Zimmer et al., 2006)
				- When injected subcutaneously, QD migrated to sentinel lymph nodes, as observed previously with larger QD, but also migrated further into the lymphatic system.
				- QD injected intravenously were shown to extravasate from the vasculature (first demonstration of this point in the literature).
CdSe/ZnS-MAA-targeting peptides ± PEG (maximal emission spectra at both 550 and 625 nm)	In absence of peptide: 3.5 nm (green) or 5.5 nm (red). Diameter with peptide not reported, but size was approx. 190 kDa.	Intravenous injection into the tail vein (mice)	5–20 min	- QD were specifically targeted to the circulatory systems of normal lungs and tumors using peptides.	Toxicity was not assessed in this study.	(Akerman et al., 2002)
				- QD also accumulated in the liver and spleen, regardless of the peptide used for targeting.
				- Adding PEG to the QD was shown to partially inhibit the nonspecific uptake of QD into the liver and spleen (suggesting the involvement of RE cells).

Note. PEG, Polyethylene glycol.