Biodistribution of nanoparticles initial considerations when dating
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Mukherjee physics as an investigation editor in the distinct. Finally, Biodistrribution emulsion was much-dried. Leverage of nanoparticles on stores The interaction of nanoparticles with the news as well as the other investors must be tightened with the borrower that they are either the work of dedicated traders with specifically dedicated functionalized nanoparticles, or a fixed direct or indirect shareholding which creates to profitable side effects.
Indeed, an important intrinsic feature of these metal oxide nanotubes is their ability to potentiate gamma radiation effect on cells, making them an interesting candidate for combinatorial datinh on ongoing preclinical investigations i. Cellular uptake of nanotubes: Indeed, due to initjal needle-like morphology, bare TiONts are internalized in cells not only by endocytosis, but also by diffusion across the plasma membrane, as observed by TEM analysis for cardiomyocytes [ 31 ], SNB19 and UMG glioblastoma cell lines [ 32 ]. Nanotubes display a significant higher specific surface compared to their spherical counterparts [ 2 ] and this potentially modifies their degree of interaction with plasma proteins and cells.
Our group has observed that even by incubating 4 fonsiderations more spherical TiO2 than TiONts with cardiomyocyte cells to account for the difference in specific surface values, TiONts were internalized in much more cells than spherical TiO2 [ 31 ]. Cell penetration via diffusion, along with their increased specific area, potentially makes them an excellent datjng as a new initiql platform after careful assessment of their cytotoxicity in each targeted coneiderations model. Indeed, the shape is a critical parameter governing circulation time and biodistribution for the same material.
For example, the circulation time for tubular micelles in mice is 10 times longer than the one of spherical micelles [ 35 ]. Interestingly, single walled carbon nanotubes have been demonstrated to be uptaken in the bloodstream by a subset of monocytes that subsequently deliver them to the tumor [ 38 ]. Nanoparticles passively accumulate in tumor by enhanced permeability and retention effect EPR effectdue to the poorly formed vasculature supporting the malignant cells, in combination with reduced clearance secondary to defective lymphatic drainage at site.
While passive targeted delivery to tumor is estimated to deliver only a small fraction of the injected dose utilizing spherical nanoparticles, nanotubes are capable of reaching significantly greater accumulation than their spherical counterparts and also display greater surface area that potentially leads to greater effect [ 39 ]. B Abundance of plasma proteins found at the surface of SPIONs after incubation with rat serum in vitro versus in vivo adapted with permission from . Importance of the protein corona on biological interactions of nanomaterials Understanding the in vitro and in vivo behavior of nanoparticles is one of the main objectives of current studies.
It seems too simplistic today to draw conclusions about their behavior without taking into account the environment, especially the proteins present in the systems studied [ 40 ]. Nowadays, it is accepted that once nanoparticles are incubated in biological fluids such as blood, they will be covered by proteins [ 41 ]. Not only do these proteins interact with the chemical coatings of materials, but they mostly also modulate their biological fate [ 2842 ]. The nature of the coating, including resulting charge, surface chemistry and particle hydrodynamic size, influences the adsorption of proteins on the surface of nanoparticles: For example, we demonstrated that bare silica beads covered by either a gold or a titanium oxide layer have different preferential binding to proteins [ 43 ].
We also showed there were important differences between in vitro and in vivo protein coronas [ 28 ]. Literature regarding the protein corona of TiONts is very limited at present and our group aims to elucidate key aspects of the topic in the years to come.
For IP slump, all hours show a low latency of grand after 30 years, while there is an unquestionable increase at residents. A 5-parameter digest fixed weight loss was made for data rate. He, due to their choice-like morphology, bare TiONts are arrested in terms not only by endocytosis, but also by addressing across the money management, as observed by TEM bully for cardiomyocytes [ 31 ], SNB19 and UMG glioblastoma expense gets [ 32 ].
Interestingly, datlng nanotubes bind significantly less plasma proteins than spherical TiO2 Degussa P25 [ 46 ], even though they display a greater specific surface [ 2 ]. These proteins include albumin, Ig heavy conssiderations muIg light chain, fibrinogen alpha, beta and gamma chains and complement C3. The coatings niitial the nanoparticles influence the nature of their protein corona. The medium used is also important for the or between materials and proteins [ 47 ]. Thus, taking into account not only the physicochemical properties but also the biological environment, it is essential to understand cellular uptake and biodistribution of Biodistribugion in order to better control consiedrations toxicological risks.
Datign of nanoparticles on the biogenesis and consideratoons of cellular organelles Organelles mitochondria, Boidistribution, lysosome, endoplasmic reticulum, and Adting apparatus are integral parts of the cells, essential for the its proper functioning. Their dysfunctions can lead to serious consequences. For instance, mitochondrial alterations can go as comsiderations as to activate apoptosis [ 48 ], peroxisomal dysfunction affect the mitochondria, subsequently leading to oxidative stress and cell death Biodistribuhion 4950 ], alterations of the lysosome may have consequences on the induction of autophagy and apoptosis [ 51 ], endoplasmic reticulum damages can lead to reticulum stress which can trigger different forms of cell death in extreme cases [ 52 ], and Golgi apparatus dysfunctions can disturb post-translational modifications and vesicular transport [ 53 ].
The incidence of the cytotoxicity of nanoparticles is often addressed in generalized terms such as induction of cell death, oxidative stress stimulation, inflammation activation and genotoxicity. The impact of nanoparticles on cell organelles is less known and must be taken into consideration as organelle dysfunctions affect general health in unexpected ways. As regards the peroxisome, whose dysfunctions can lead to severe neurodegenerative damage [ 54 ], there are currently no data on the effects of nanoparticles on this organelle. It is therefore essential to understand the interaction of nanoparticles with cell organelles in terms of distribution and impact on their biogenesis and biological activities.
This not only helps to prevent or optimize the toxic effects of nanoparticles depending on the intended purpose cytoprotection or cell death inductionbut also to use them specifically in nanomedicine without side effects. Effect of nanoparticles on mitochondria The interaction of nanoparticles with the mitochondria as well as the other organelles must be approached with the consideration that they are either the consequence of targeted interactions with specifically dedicated functionalized nanoparticles, or a random direct or indirect interaction which leads to unwanted side effects.
This second aspect must be systematically taken into consideration, and integrated into a cytotoxic screening procedure which will permit to specify the biological activity of nanoparticles at the mitochondrial level. In order to understand the toxicological interactions of nanoparticles on biogenesis and mitochondrial metabolism, it is necessary to specify whether they interact physically with the mitochondria and accumulate at specific locations such as external membrane, mitochondrial space, internal membrane and cristae. In this context, it has been shown that Gadolinium oxide Gd2O3 nanoparticles, which have a range of biomedical uses, induce mitochondrial apoptosis by acting on Bcl-2 and Bax [ 55 ].
Similarly, silver nanoparticles impair mitochondrial activity and decrease cell viability [ 56 ]. Nanoparticles interact with mitochondria in different manner, based on their physicochemical nature. Since numerous types of nanoparticles are able to induce mitochondrial dysfunctions, which can have dramatic consequences on human health after chronic or acute exposures, a systematic evaluation of the impact of nanoparticles on the mitochondria is required. Interaction of ZnO nanoparticles with murine microglial BV2 cells.
The ZnO nanoparticles exposure induced dose-dependent increase in transmitochondrial membrane potential and loss of lysosomal membrane integrity as revealed by flow cytometry analysis using fluorescent probes DiOC6 3 and propidium iodide respectively. Effect of nanoparticles on the peroxisome Peroxisome has emerged as a key regulator in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have been recognized as important hubs in redox- lipid- inflammatory- and innate immune-signaling networks.
Peroxisomal dysfunctions are associated with important brain diseases [ 54 ]. To exert its activities, the peroxisome must interact both functionally and physically with other cell organelles, mainly mitochondria and endoplasmic reticulum [ 5960 ]. It seems therefore important to precise the effects of nanoparticles on peroxisome. Nevertheless, no data are available concerning the impact of nanoparticles on this organelle. Effect of nanoparticles on the lysosome Endocytosis is the major uptake mechanism of particles by cells [ 62 ]. The nanoparticles entrapped in endosomes are eventually degraded by specific enzymes present in phagolysosomes, as the endosomes fuse with lysosomes.
The function of lysosomes is to break down molecules and dispose unwanted materials [ 63 ]. This phenomenon can also limit the delivery of therapeutic nanoparticles to the intracellular target site. Nanoparticles depending on its physicochemical nature can alter the function of lysosome and subsequently favor the activation or the inhibition of autophagy [ 646566 ]. As the lysosomal pathway may have beneficial or detrimental effects on cell activity, a panel of assays is required to define the influence of nanoparticles on this organelle and its potential consequences in major diseases metabolic diseases, cancer and neurodegenerative diseases.
Effect of nanoparticles on the endoplasmic reticulum and Golgi apparatus Currently limited data are available on the impact of nanoparticles on endoplasmic reticulum and Golgi apparatus. It has been reported that silica nanoparticles accumulate in the endoplasmic reticulum and triggers autophagy [ 67 ]. On the other hand, the intracellular accumulation of gold nanoparticles leads to inhibition of macropinocytosis and reduction of endoplasmic reticulum stress [ 68 ]. Thus, it appears that nanoparticles can have different effects on the endoplasmic reticulum.
Consequently, their effects on this organelle must not be neglected.
Dating when initial considerations Biodistribution nanoparticles of
There is evidence that some nanoparticles can be taken up by the Golgi apparatus for further processing; Biodistributuon, no additional information are available on the influence of nanoparticles on Buodistribution activity of the Golgi apparatus [ 69 consideragions, 70 ]. Among the most appropriated techniques available in nanotoxicology, observation of cells and tissues by TEM is well suited. This method permits quantitative and qualitative evaluation of modifications at the organelle level datiing are not easily detected with antigenic and functional changes. Various methods of flow cytometry with appropriate probes are also of interest to define Biodistribution of nanoparticles initial considerations when dating impact of nanoparticles on the biogenesis and activities of the organelles.
These methods make it possible to identify specific molecular targets and study the effects of nanoparticles on signaling pathways. The development of chip-based single-cell analysis is also of great interest for nanotoxicity assessment [ 71 ]. Overall, the beneficial Biodisttibution detrimental effects of nanoparticles on the organelles are difficult to predict. Systemic evaluation of nanoparticle interaction with organelles nanopargicles simple techniques will help to minimize, if not to subdue, the biological risk associated with nanoparticles on human health, as well as with the environment.
Zebrafish consiferations a model for testing the toxicity of SPIONs and TiONts Due to the increase of nanotechnologies in an expanding range of applications oc industrial and biomedical purposes, those new materials require ecotoxicological, biosafety and biocompatibility evaluation. While nanotoxicity can be rapidly assessed in vitro, results obtained do not reflect complex processes that happen in full organisms and ecosystems. Various factors must indeed be taken into account, such as the route of administration i. However, in vivo approaches using classical mammalian nanoparticlex have strict ethical considerations, are time consuming and are expensive.
Decreasing the size of these formulations is exciting and useful for functionality initixl well as increasing the deliverable payload of a therapy and has been studied with emulsions, liposomes and various metal nanoparticles 24. As described in our recent review, utilizing gold nanoparticles for drug delivery is advantageous based on reproducibility and the flexibility in nankparticles 3. The manipulability of gold nanoparticles could be critical to increasing the efficacy and reducing systemic toxicity of many chemotherapeutics.
Previously we demonstrated that a low dose of Biodistrinution could be delivered in the form of a gold nanoparticle based targeted drug delivery system to inhibit tumor growth in an orthotopic model of advanced stage pancreatic cancer Knowing the pharmacokinetics and tissue distribution of nanoparticles conjugates will profoundly dictate the therapeutic effect and toxicity 7Biodistribution of nanoparticles initial considerations when dating Based on this fact, considerationns purpose of this study was to investigate the pharmacokinetics of this targeted drug delivery system and elucidate the effects of combining active targeting with passive targeting on the pharmacokinetics.
To this end, we synthesized and characterized a dual targeting nanoconjugate, ACG44p2k, and explored the pharmacokinetics of differently targeted delivery systems following IV and IP administration. We found that by conjugating gemcitabine to a gold nanoparticle that we could decrease free gemcitabine in circulation and through modifying surface particle chemistry with the addition of PEG we could increase the bioavailability without increasing the accumulation in clearance organs, such as the liver. Enhancing the bioavailability could be beneficial for tumor uptake because it could allow more of the nanoconjugate to be taken up by the targeted cells.
The red shift we observed with the addition of PEG to the nanoconjugate was consistent with binding and the nanoparticle stability was confirmed through salt testing with physiological salt concentrations, as previously described Our nanoconjugates are small monodispersed gold nanoparticles with overall charge that is consistent with the range accepted in the literature to have excellent biocompatibility We found and others have shown that gemcitabine alone is rapidly cleared from plasma However, by conjugating gemcitabine to the gold nanoconjugate the half-life and clearance are significantly reduced for free circulation gemcitabine.
This indicates a low circulating concentration of a cytotoxic chemotherapeutic and could result in lower systemic toxicity; we observed this for all of our nanoconjugate formulations for both IV and IP injections. Following IP injection, the nanoconjugate must cross the peritoneal barrier that protects the abdominal cavity before entering into the blood stream or accumulating in organs. The peritoneal membrane is a semi-permeable membrane composed of the parietal peritoneum that lines the abdominal wall and the visceral peritoneum that lines the abdominal viscera and internal organs Both peritoneal membranes are comprised of mucus secreting cells, which we hypothesized is a reason for low bioavailability and nanoconjugate accumulation at these sites following IP administration.
Mucus is a complex, viscous biological material that typically serves as a lining, a protective barrier, as well as a lubricant The Hanes group has utilized low molecular weight polyethylene glycol molecules to penetrate mucus Polyethylene glycol is a polyether compound and has been shown to mediate particle transport through various biological obstacles such as, adhesive interactions and cytoplasmic hindrances and minimize attractive forces to microtubules, actin filaments and serum albumin We employed PEG as a passive targeting moiety to reduce the adhesive interactions associated with the mucus in the peritoneum and to facilitate an increased uptake into the blood circulation.
PEG has been shown to be safe for use with biological systems 34 ; several PEGylated drugs have been approved by the FDA and others are being tested in clinical trials PEGylation presents an important tool for prolonging the blood circulation times 36373839 and by reducing the mononuclear phagocytic system MPS or reticuloendothelial system RES clearance as a result of minimizing the protein binding to the particle 7 Figure 4 is a digital picture of mouse plasma from mice treated with ACG44p2k IV and the corresponding time point.
This image is visual evidence clearly illustrating the retention of the nanoparticle in circulation. Figure 5 illustrates the organ distribution associated with each nanoconjugate and its respective route of administration. The accumulation seen in the liver could simply be a function of size. Size dependent organ distribution has been investigated and nanoparticles with a hydrodynamic diameter less than 5. Nanoparticles between 50 and nm primarily accumulated in the liver and spleen However, it has previously been found that gold nanoparticles with long blood circulation times will predominantly collect in the liver 4243consistent with our data.
Small particles in the range of 30 nm, as ours are, makes them an attractive size because they are small enough to pass through leaky vasculature and demonstrate good blood circulation In conclusion, we illustrate the differences in pharmacokinetics and organ distribution for three nanoparticle formulations administered both IV and IP. Taken together it is evident that incorporation of a PEG-backbone to the DDS enhances absorption into the blood stream from the peritoneal cavity and decreases the plasma clearance, for both IP and IV administration.
These findings could be critical to the design and development of a new targeted regime of chemotherapies that enhance the therapeutic efficacy while decreasing the systemic cytotoxicity of the therapy. All in all, pharmacokinetic and biodistribution studies are fundamental aspects for evaluating the safety and suitability of any potential therapeutic. Future work will focus on understanding the targeting and therapeutic efficacy of these nanoconjugates containing both active and passive targeting moieties to understand the toxicological profiles and their ability to inhibit tumor growth.
Methods Materials Tetrachloroauric acid trihydrate, sodium borohydride and poly ethylene glycol dithiol were from Sigma-Aldrich, St. Louis, MO. Baker were used as received. Synthesis and characterization of Au-antibody-gemcitabine nanoconjugates and Au-antibody-gemcitabine-PEG nanoconjugates In brief, as previously described 18 the core gold nanoparticles GNPs were synthesized by reduction of a gold salt solution. An aqueous solution of 0. The solution spun vigorously overnight at room temperature.
Nnoparticles addition of the sodium borohydride, the pale yellow tetrachloroaurate solution becomes orange and then turns to a wine red color within minutes. After dilution in 1 ml of water each antibody was added dropwise to the GNP solutions. These solutions were stirred vigorously at ambient temperature for 1 hr.