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«COLLOIDAL GOLD NANOPARTICLES FOR CANCER THERAPY: EFFECTS OF PARTICLE SIZE ON TREATMENT EFFICACY, TOXICOLOGY, AND BIODISTRIBUTION A Dissertation ...»

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Even though equal gold concentration was injected for both 5nm and 60nm gold systems, small-sized 5nm gold system exhibited less uptake by the liver and the spleen.

Furthermore, less gold was retained for 5nm gold system after 180 days that there was a significant decreased in the gold concentrations in the liver and the spleen, whereas 60nm gold system displayed minimal decrease and increased retention of gold in the liver and the spleen. We believe that the size plays a critical role in the biodistribution and clearance of the nanoparticle over time.

Indeed, previous literature supports our size dependent biodistribution and clearance results. It has been reported that when four different sizes of gold nanoparticles (10, 50, 100, and 250nm) were intravenously injected in rats, 10nm gold nanoparticles were found in all organs evaluated (total gold amount highest in liver blood spleen kidney lungs brain testis heart) whereas 50, 100, 250 nm gold nanoparticles were almost solely distributed to liver, spleen, and blood after 24 hour of injection [49].

Similarly, when 15, 50, 100, and 200 nm gold nanoparticles were injected intravenously in mice, smallest 15nm gold nanoparticle resulted in a wide spread of gold in liver, lung, kidney, spleen, brain, heart and blood; particles larger than 50nm were mostly confined to the liver, lung, kidney, and spleen after 24 hours [60]. Finally, the accumulation of 1.4nm gold nanoparticles in the liver and spleen was significantly lower compared to that of 18-nm gold nanoparticles where twice as more total injected gold accumulated in the liver and spleen for 18nm gold nanoparticle [205]. Similar to our 5nm gold nanoparticles, smaller 1.4nm resulted in wide spread in the system where 1.4nm gold nanoparticles accumulated in liver, lung, spleen, kidney, brain, heart, and skin in rat.

As seen with our 5nm versus 60nm gold system study, majority of gold was accumulated in the liver and the spleen. Previous studies reports accumulation of gold in the liver and the spleen for long durations of time regardless of size, shape, dose, and types of materials. 10-20nm carbon nanotubes in mice resulted in 80% and 5% of total gold in the liver and the spleen, respectively, at a nearly constant level throughout 28 days [211]. Single injection of 13nm quantum dot, coated with MW5000 methoxy PEG, resulted in accumulation in the liver (29-40% of the injected dose) and spleen (4.8-5.2% of injected dose) over 28 days [212]. Similarly, iron oxide (11 nm) injected in rats resulted in 50 % and 25 % of injected dose in liver and spleen after 21 days [213]. When gold nanorods (65nm in length and 11 nm in width) were injected intravenously, 35 % of total gold accumulated in the liver and 2 % in spleen after 3 days [51]. Within 24hr, 18nm gold nanoparticle AuNP was completely removed from the blood and predominantly present in the liver (93.9% of injected gold) then in spleen (2.2% injected gold) [205]. Injected gold nanoparticles of four sizes (10, 50, 100, and 250nm) in rats resulted in accumulation mainly in the liver (20-46% injected dose) an spleen (1.2-2.2% injected dose) after 24 hours [49]. When 12.5nm gold nanoparticle was injected everyday for 8 days intraperitoneally, gold nanoparticles accumulated in various organs (amount of gold/ gram of tissue being spleen liver=kidney lungs brain) with liver having the highest total % of injected gold [214]. For long term studies like ours, Sadauskas, E. et al.

reported that intravenously injected 40nm gold nanoparticle was removed from the circulation primarily by the Kupffer cells in the liver and remained as clusters even after 6 months [58]. Study from a company called CytImmune also reported intravenous injection of 27nm gold nanoparticle coated with TNF-α and PEG in a tumor mouse model resulted in gold uptake by the liver and spleen (~35% of the total gold) at 120 days [197].

The significant and persistent accumulation of gold nanoparticle in liver and spleen through intravenous exposure could be due to their fenestrated, discontinuous endothelia which allow nanoparticles up to 100 nm in diameter to exit from the bloodstream into the parenchyma. In addition, organs of the reticuloendothelial system (RES) including the liver and spleen can efficiently accumulate nanoparticles via opsonization that nanoparticles could bind to antibody in the plasma and are subsequently recognized by the phagocyte-rich RES [215]. Also, higher uptake in the liver could be due to (1) larger organ size and (2) the momentary saturation of the uptake capacity of the spleen, which allows uptake in the liver when high concentrations of gold nanoparticles are introduced in a bolus intravenous injection. From various studies reported in the literature, several factors such as particle size, their surface charge, surface hydrophobicity, and the presence and/or absence of surface ligand are responsible for particle uptake by the RES [200].

(a) (b) Figure 5.4. TEM Images of (a) 5nm and (b) 60nm Gold Nanoparticles in Various Organs at 6 Months TEM images in Figure 5.4 show 5nm and 60nm gold nanoparticles present in small clusters in the various organs of liver, spleen, and kidney at 6 months. Most of the gold nanoparticles are contained in a membrane-bound vesicles inside irregularly-shaped (suspected to be macrophages) cells. The arrangement of nanoparticles in the sample indicated that the clusters were most likely agglomerates with weak binding forces. After intravenous administration, the gold nanoparticles may have been covered with various proteins present in the blood such as serum albumin and apolipoproteins that may facilitate the cellular uptake of the nanoparticle, as demonstrated for polymeric nanoparticles [216]. It has been observed that nanoparticles are rapidly uptaken, sequestered, and retained by the RES, mainly in the liver and spleen [200]. In the liver, the particles are mainly retained by the scavenging periportal and midzonal Kupffer cells, while hepatocytes and liver endothelial cells may play a secondary role under special pathophysiolgical conditions. It has been reported that Kupffer cells in the liver are mainly responsible for uptaking polymeric nanoparticles with hydrophobic surface. In the spleen, the marginal zone and red pulp macrophages are the major scavengers, while peritoneal macrophages and dendritic cells have a minor contribution.





Clearance of Gold Nanoparticle Generally, renal and hepatobiliary systems are involved in the clearance of nanoparticles via urine and feces. Renal clearance or urinal pathway is more desirable that kidney is capable of rapidly removing the nanoparticles from the vascular compartment in an unaltered, original form [217]. There is minimal involvement of intracellular catabolism associated with the renal route that minimizes toxicity and agent retention. In contrast, hepatobiliary system requires intracellular enzymatic modification.

In hepatobiliary clearance, hepatocytes are directly related to bile excretion, and Kupffer cells are responsible for intracellular degradation of uptaken nanoparticles [217]. The uptake of hepatic system is quick, with the preferential uptake of particles in 10-20nm size range, but the hepatic clearance is a very slow process and most of the time nanoparticles result in prolonged retention in parenchyma itself [64, 217].

Various studies have been reported for clearance of nanoparticles. For 1.9nm gold nanoparticle, ~77% of the injected gold was excreted through kidney within 5hours in mice [56]. Choi et al. also reports rapid clearance of zwitterionic quantum dots (4.36nmnm) within 4 hours of intravenous injection through kidney [64]. 1.4nm gold nanoparticle were both excreted by kidney and hepatobiliary systems (8.6% injected gold in urine and 5% injected gold in feces), whereas 18nm gold nanoparticle resulted in relatively small hepatobiliary excretion (0.5% injected gold) and hardly any renal excretion in rats [205]. 13nm quantum dots displayed accumulation in kidney without any renal excretion [63] when 13 nm PEGylated gold nanoparticle accumulated in the liver and spleen without any hepatobiliary excretion up to 7 days [55]. Interestingly, larger 27nm PEGylated gold nanoparticles were significantly cleared out from the liver via hepatobiliary clearance after 4 months of intravenous injection in mouse [197]. Also, Balasubramanian et al. found that 20nm gold nanoparticle filtered from the bloodstream and excreted via urine (1.7ng/g at day 1 and 0.8 ng/g at 1 week) [52]. It is puzzling to see various sizes of nanoparticles get cleared out, especially via renal filtration, when the literature reports effective pore size of the filtration barrier (i.e. glomerular basement membrane (GBM)) and podocytes to be ~8nm in the kidney [218]. Thus, it is not only the size but also other factors like charge affects the clearance of nanoparticles.

As seen in Figure 5.5, our 5nm gold nanoparticle coated with MW 5000 thiolated methoxy- PEG (average hydrodynamic diameter of 18.2 ± 0.9 nm) resulted in both renal and hepatobiliary clearance. Since urine and feces were collected at the indicated, particular time point (i.e. not cumulative), we can not conclude how much of the total injected gold was excreted via urine or feces. However, it is clear that our 5nm gold system was significantly excreted via urine and feces up to 25 days. We believe that 5nm gold system was excreted rapidly via urine and feces at the initial time point (~ up to 9-10 days) and rest of the 5nm gold system was excreted slowly as gold nanoparticle accumulates in the kidney, liver, and spleen. It has been reported that PEGylation dramatically reduces particle renal filtration due to increased hydrodynamic diameter (HD). Cho et al. reported that PEGylation of 4nm gold nanoparticle (HD of 14.8 ± 3.3 nm) resulted in hardly any renal and hepatic excretion [210]. In contrast to our results, they concluded that PEGylated 4 nm gold nanoparticle had a similar excretion profile as larger 13nm and 100nm PEGylated gold nanoparticles. Even though we are unclear of the exact mechanism at which allowed the passage of 5nm PEGylated gold nanoparticle through renal filtration, we believe that the successful excretion of 5nm PEGylated gold nanoparticle, particularly in renal system, was due to the surface charge (Cho et al. does not report the zeta potential or the MW of PEG used for their system) and perhaps coating replacement. It has been reported that filtration is greatest for cationic then neutral then anionic molecules being the least [217]. Molecular charge is of particular significance for molecules within 6-8nm range, as these particles are not small enough to undergo charge-independent filtration, yet may still be filtered if molecular charge is favorable. The fact that our 5nm gold system is excreted, however, suggests that factors other than pore size may be important in the filtration of nanoparticle. The effective filtration pore diameter of 8nm applies to proteins with negative charges which are effectively repelled from the GBM barrier. The neutral or slightly negatively- charged 5nm gold nanoparticle may not be so effectively repelled, and manage to pass through the barrier. It has been reported that hydrodynamic diameter greater than 15nm cannot be excreted renally [64]. Furthermore, unlike the hard 5nm core, the shell created by PEG is soft and flexible that might have changed its conformation, thus allowing the passage of gold system. PEG coating on the surface of the gold might have been replaced with other ligands in the serum (i.e. proteins) that could have led to alteration of shape, charge, and hydrodynamic diameter of our gold system. Finally, high concentrations of gold injected into the mice have resulted in excretion of gold via urine and feces, where high concentration gold resulted in the uptake capacity of the RES. The slight decrease in the rate of urine excretion in the later phase might suggest gradual accumulation of nanoparticles in the kidney over months might diminish the permeability of GBM and podocytes, further reducing the excretion of gold nanoparticles.

Hepatobiliary excretion of gold nanoparticles have been reported by Renaud et al.

that colloidal gold taken up as a complex with low-density lipoprotein was excreted into the feces via the common bile duct at a maximal rate of about 5% daily, 4 to 12 days after injection [219]. Hardonk et al. also reports excretion of gold nanoparticles via hepatocytes at the earlier phase then via Kupffer cells at later phase [220]. For chrysiasis in humans, gold salt, concentrated particularly in the RES, are excreted in feces and urine continuing for years after cessation of the therapy [208]. Excretion profile of 60nm gold nanoparticle was excluded, as previous literature reports hardly any excretion of larger particles via urine and minimal excretion via hepatic system [58, 210].

(a)

–  –  –

Figure 5.5.

Renal (a) and Hepatobiliary (b) Clearance of 5nm PEGylated Gold Nanoparticle [each time point represent urine or feces collected at that particular time point (i.e. not cumulative)] Previous research study states that given the same surface chemistry and similar chemical properties/composition of the gold core, the size governs the uptake by the lymph nodes [221]. This was consistent with our study where small-sized 5nm gold system was visible as dark brown circle in the extracted lymph nodes (Figure 5.6).

Initially, dark brown circles were visible within the lymph nodes and as the time progressed, the pigmentation of the dark brown circle in the lymph node lightened up.



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