Research on oncological and oncological related treatments has contributed to the production of a number of drugs that target systematic biomolecules, such as DNA, which generally have high toxicity. Some of the drugs have poor non-selective biodistribution properties and limited solubility, severely damaging the tissues (Peer et al., 2007). As early as 1986, there had been attempts to use enhanced permeability and retention (EPR) effects for the oncological treatments (Matsumura & Maeda, 1986). The EPR effects enhance permeability of tumors when they are in contact with macromolecules; when macromolecules enter tumors, they are retained due to limited recovery of blood vessels. Following the success of the EPR research on tumor targeting and accumulation of synthetic and natural macromolecular carriers, more advanced research has been conducted (Matsumura & Maeda, 1986). More recently, scientists have used different nanosized delivery platforms, such as polymeric nanoparticles, inorganic nanoparticles, and liposomes to improve the therapeutic and pharmacological properties of the drugs (Youns et al., 2011; Peer et al., 2007). Carbon nanotubes (CNTs), which are frequently used by researchers, are among the most common delivery platforms (Endo et al., 2008). This paper analyses selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumor delivery, as researched by Smith et al (2014). The paper discusses the biological, thermodynamic and transport aspects highlighted in their investigation (Smith et al., 2014). In addition, the paper addresses the contributions of Smith’s et al. (2014) research, considering the current literature on biotechnology.
Carbon nanotubes are tubular allotropes of carbon. They are usually well-ordered, with their diameters ranging in nanometers and lengths ranging in centimeters (Meng et al., 2012). When they are envisioned as a single graphene sheet, which is usually rolled into a seamless tube, then they are termed single-walled carbon nanotubes (SWCNT) [The current study largely focuses on SWNTs]. On the other hand, some are envisaged in multiple-layer graphene, rolled simultaneously in concentric tube shapes, commonly referred to as multi-walled carbon nanotubes (MWCNTs).
Recently, there has been extensive research on the uptake of single-walled carbon nanotubes. In one of the significant researches in the history of nanotechnology, Smith et al. (2014) describe the exploitation of the body’s immune system and drugs encased in nanoparticles (single-walled carbon nanotubes [SWNTs]) to study how the last are taken up by monocytes, with selective delivery to the tumor. The technique may be helpful in fighting diseases such as cancer, diabetes, and atherosclerosis. Smith’s et al. (2014) research focuses on the modalities via which SWNTs are rapidly absorbed by a key subset of the biological material, known as Ly-6Chi monocyte, and then delivered to tumors.
Analysis of the Paper Hypothesis
This paper seeks to analyze Smith’s et al (2014) research hypothesis on the uptake of SWNTs into tumors. As projected by the researchers, the main hypothesis is to ‘identify and characterize mechanisms that mediate the uptake of SWNTs into tumors through dynamic imaging on the microscale and determine if the mechanisms are ligand-mediated in nature’. The current study hypothesis deviates from the objectives of the previous research, which are based on the idea that blood cells take up nanoparticles for deposition into tumors, depicting increased uptake as a result of ligand targeting. The Smith’s et al (2014) research hypothesis, as analyzed in the current study, uncovers the optional tumor uptake mechanisms with a possibility of opening up new approaches to increasing deposition of nanoparticles in tumors. In addition, the exhaustion of the current hypothesis provides basis for improving tumor diagnosis methods, oncological treatments, and related applications.
The research findings of the current study suggest a nanoparticle approach to disease treatments and initiate investigation on the cell-based delivery of nanotherapeutics. Initially, the research on the delivery of nanomedicine had failed to conclusively identify an efficient way of transporting nanoparticles to the oncological disease sites (Maeda, 2013). The most significant finding of the research is that Ly-6Chi immune cells can naturally penetrate oncological tissues, enabling intended deposition of nanoparticles. Unlike the Trojan horse approach, the nanotube approach may be used for the treatment of nearly all solid tumors.
The research has revealed that the circulating blood cells can rapidly internalize SWNTs. The research involving single-wall carbon nanotubes (SWCNTs) in live mice has been done with the help of an ‘intravital’ microscope to image and record videos of how nanoparticles interacted with cells. Smith’s et al. (2014) research has demonstrated that the mice cells wolfed the nanotubes that circulated in the blood stream. In previous biodistribution and nanomaterial studies, Cai, Shin, Chen, Gheysens, Cao, Wang, Gambhir, and Chen (2006) and Liu Davis, Cai, He, Chen, and Dai (2008) revealed gobbling up of SWNTs in some organs of the mice, which suggests internalization of the SWNTs within the circulating blood systems of these animals. Consequently, the current study by Smith et al. (2014) has supported the earlier suggestions that SWNTs can enter the tumor through uptake of cells that circulate in the blood. The delivery mechanism may account for up to 25 % of the SWNT to the tumor.
In oncology, the SWNT uptake mechanism is highly important because it is less affected by the EPR. It has huge extravasation heterogeneity that is present in various types of tumor, specifically human tumor types. The most reliable mechanism for selective delivery of nanoparticles through the blood cells to the tumor is the Trojan horse mechanism. The method is typically the most reliable when it concerns solid tumors in . Therefore, it is easier to translate diseases relating to humans for purposes of therapeutic and diagnostic efficacy (Murdoch et al., 2004). The other significant importance of the mechanism is its ability to reach necrotic and hypoxic tumor regions. It has been impossible to reach these regions via the vascular system by delivering nanoparticles through the distinctive targeting mechanism. The possibility has been brought about by the ability of tumor-associated macrophages (TAMs) and Ly-6Chi to be attracted to and be differentiated in the necrotic/hypoxic tumor regions. Those regions are therapeutically critical since they may allow SWNTs to access the repellent tumor cells. Still, the other advantage is that there is no restriction on nanoparticles due to the time of circulation during uptake into the tumor. However, the only restriction is based on time of circulation when they are taken up by the immune cells in the blood. Consequently, it means that there will be a constant delivery of nanoparticles for a number of days. In addition, despite the fact that the delivered nanoparticles are said to be able to directly bound to tumor cells without any problems, the findings indicate that there is a notable percentage of their sequestering in macrophages/monocytes. Therefore, it can be reasonably assumed that they are not capable of attaching themselves to the surface of tumor cells, except if they are finally released (Murdoch et al, 2004).
The neutrophils represent 52% of the total number of the cells present in the blood (the cells cluster in the higher right corner gated as neutrophils; neutrophils proportion taking up SWNTs is represented by the plots located by the row in the top right corner). The lower left plot gates are non-neutrophils. The cells displaying high CD11b and Ly-6C levels (cells amidst non-neutrophils), are gated in the plot towards the extreme left of the 2nd row in right upper corner, the inflammatory monocytes (Ly-6Chi monocytes). The selective uptake of SWNT into Ly-6Chi monocytes is described by the 3 plots in the second row to the right (almost all the blood monocytes at 2-hour-take up SWNTs middle right plot. Below 3%, the rest of the subpopulations in the blood, including neutrophils, take up SWNTs.
The analysis shows that the cells are remnants of the removal of Ly-6Chi monocytes and neutrophils. The plot is composed of cells that include Ly-6Clow monocytes, CD11+population (dendritic cells), and Natural killer cells. The plot data of the cytometry represent a sample of groups of n=5 mice. Numbers closer to the gates stand for the plot’s proportion of cells available in the drawn gate. The drawing of the gates was done on the basis of fluorescence less 1 (FMO fluorescence minus one) negative controls.
Further findings suggest that independence from EPR by the nanoparticles taken up through this targeting mechanism into the tumor shows that there is a similar independence from concerns of the critical EPR by nanoparticles as well. The above properties depict nanoparticles’ ability to enter into monocytes. Therefore, there is the need to find out if other types of nanoparticles, such as iron oxide and quantum dots nanoparticles, could be successfully delivered in the same way or in a way that is closely similar to the discussed method. Smith’s et al (2014) paper does not provide an example of a procedure through which the delivery of the nanoparticles can be done without taking into account and preventing alteration of the ability/property of nanoparticles to enter monocytes (Smith, et al. 2007).
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Apart from being of great significance, it is dependent only on the natural monocytes’ horning. The findings imply that the monocytes’ deposition in tumor is amplified on the SWNT surface by the RGD, thereby the quantity of delivered SWNTs is increased due to the total SWNT accumulation proportion and the number of SWNT.
The raised rate of infiltration could be a result of vascular endothelial surface and RGD interaction. The monocytes uptake was approximated between 10 to 25% of the total number of SWNTs within the tumor. It is due to the variation in the type of the used peptide, making it a component of major tumour targeting. The reason behind this could be explained by constant SWNTs accumulation since SWNT-loaded monocytes continue their accumulation in the interstitium of the tumor between 7 and 9 days. This is reliant on the observed Raman imaging trends of SWNTs intrinsic signal and intravital microscopy (Yeste et al., 2012).
The possibility to increase the speed of monocytes uptake to tumors can be utilized to enhance the therapy of immune-mediated cancer by making use of various therapeutic strategies, possibly incorporating the evocation of monocytes into tumoricidal form (Murdoch et al, 2004). This property shows that there is a possibility that it can be applied in imaging or destroying tumors by making use of nanoparticles to reprogram them. Since the macrophages by CD40activated cells are tumocidal and the differentiation of Ly-6Chi monocytes into macrophages occur in the tumor, activation molecules may be combined with SWNTs to make the activation trigger of the nanoparticle stronger (Cubillos-Ruiz, Engle, Uciane, Martinez, Barber, & Elgueta, 2009). The RGD could also be utilized to raise the amount of macrophages in order to gain easy destruction of the tumor.
The goal, which has been pursued for a long time for various applications in the medicine industry, is the ability to directly select drugs and nanophytes to be delivered into the immune cell to circulate . The attempt has seen major selective uptake, which was exceedingly difficult in either optimized or normal conditions A variety of strategies exhibit a quite easy uptake through a number of immune cells. Ly-6Chi is one cell in the group of premier cells that increases the delivery of nanoparticles to the sites of the disease in general. Apart from that, it also assists in therapeutic and imaging interventions by enhancing the development of novel routes (Murdoch et al, 2004).
The property that gives them this ability is their indigen phenotype that is responsible for enhancing the infiltration of tissue affected in a wide variety of diseases through the Trojan horse mechanism, for example, cancer (Leuschner, et al. 2009). Ly-6Chi monocytes are distinctively functionally different from the rest of monocyte subsets; phenotypically and physically, the distinction is constant even with Ly-6Clow monocytes within the blood. In addition, the proportion of Ly-6Chi monocytes is between 2 and 5% of the total number of white blood cells in circulation (Cubillos-Ruiz et al., 2009).
In the cancer treatment application, to target this monocyte subset is advantageous as the differentiation of Ly-6Chi to TAMs is possible. TAMs are vital components in the stroma of the tumor. In cancer pathogenesis, specifically TAMs have been entailed, which calls for creation of new strategies that could be possibly provided by selective SWNT targeting (Roy, 2010). TAMs are difficult to reach due to their position in the hypoxic region, deep in the tumor, so the injection particles could not reach them. The critical limitation could however be avoided in the blood by targeting Ly-6Chi. These kinds of SWNTs penetrate monocytes within the blood, which incur diapedesis to become TAMs in the tumor interstitium, TAMs then transport them to the hypoxic region of the tumor (Leuschner et al. 2009). The approach avoids the method of ex vivo labelling, which is achieved by directly injecting intravenously, however the method may be reserved as an alternative for increasing SWNTs delivery into the tumor (Cruz, Rueda, Cordobilla, Simon, Hosta, Alberico, & Domingo, 2011). Eventually, with regards to the resultant clinical translation of the human, it is clear that murine Ly-6Chi monocytes exhibit high genetic functionality and homology to subset CD14hiCD16, a correspondent subset of human monocytes (Cubillos-Ruiz et al. 2009).
The operation mechanism through which SWNTs monocytes are selected to Ly-6Chi is not yet clear. The high frequency of targeting the tumor by monocytes through RGD is not sufficiently understood, however, the implication from imaging data is that it could be the result of interaction between vascular endothelium of the tumor and RGD (Leuschner et al. 2009). From the findings explained so far, the research does not take into consideration the possible toxicity of SWNT, which is a matter of great concerns. Nevertheless, tt has been found that efficient selectivity entails that Ly-6Chi monocyte is the most likely main type of cell of concern, even though there is a chance that such inflammation could come up through monocytes indirectly, as a result of antigen presentation and release of cytokine.
Smith’s et al. (2014) research is unique because other researches have depicted nanotube’s deleterious effects (the example is non-functionalized, multi-walled nanotubes) on monocytes (Cubillos-Ruiz, et al. 2009). In this research, the 6 h p.i monocytes are not activated by biocompatible single-walled nanotubes, showing that monocytes are not significantly affected by SWNTs with regards to the analysis of surface marker. SWNTs seem both non-toxic to mice and monocytes in general, although they can be therapeutic/protective to tissues whose sensitivity is equal to that of the brain. An immediate goal now is to work on deeper understanding of the operation of the mechanism and SWNTs’ effects on monocytes.
As highlighted earlier in this report, the study by Smith et al. (2014) suggests progress in the nanotechnology research. Throughout the research report, a number of issues significantly illustrate this topic. Evidence by Smith et al. (2014) on how Ly-6Chi takes up nanotubes has not been clearly investigated by earlier researchers to a remarkable degree, highlighting the current research as a milestone. More significantly, the research team reveals that the targeting ligands (RGD peptides), which conjugated to nanotubes, may serve to enhance the number of SWNT loaded monocytes that reach the tumor. In an earlier similar study conducted by Meng et al. (2012), the researchers explored drug delivery vehicles (targeting doxorubicin to tumors), but did not mention RGD peptides. Consequently, this significant experiment suggests how RGD peptides attachment to SWCNTs can remain on the surface of monocytes even after nanotube take-up. A section of the suggestions from Smith’s et al. (2014) research concurs with the previous researches, particularly on manipulating monocytes. RGD peptides can bind with the tumor blood vessels; implying that RGD nanotubes and loaded monocytes appear to target the tumor in some kind of molecular address system that enables them to bind selectively to the tumor blood vessels via RGD.
This work does provide the analysis for the research to assess the toxicity of SWCNTs with a highly packed protein-coating. There is basis for making comparisons to critique the paper. According to the research, the highly competitive protein layer bound to SWNTs’ surface has effects on the interaction of the cells and the subsequent responses of the cell. Additionally, BFG, Tf, Ig, and BSA-coated SWNTs were seen to cause minimal cytotoxicity compared to uncoated SWNTs. On the other hand, SWNTs coated with BFG hardly had any toxicity. The way in which the absorbed proteins are re-arranged on SWNTs has the effect on the level of toxicity of SWNTs. The unique feature of BFG protein is its ability to rearrange themselves on the SWNTs’ surface with the maximum number of layers and with the most compact figure (other proteins form two or three layers but BFG forms five layers, thus being responsible for its compact nature). This quality may be a protection of the cells against SWNTs’ surface exposure.
The research has managed to disclose a novel, critical mechanism for uptake of nanoparticles into tumors that accounts for substantial percentage of the entire uptake into tumors. The most significant achievement of this research is that it has identified and established that SWATs target one most important monocyte subset in the blood keen selectivity and also that RGD ligands bonded to SWNTs can be utilized to intensify the cell delivery into sites of the tumor, effectively ‘conditioning’ them to get into the interstitium of the tumor.
This work is anticipated to be of great and advantageous implications in the medical industry, particularly nanoparticle cancer applications. The applications may include cancer treatment and detection in the clinic. Also, it spotlights the utility of making use of targeted delivery of the circulating monocytes, owing to their ability to enter with ease and travel all around tumors. Furthermore, there is a significant aspect concerning precise Ly-6Chi monocytes preclinical identification for biological and disease studies. Finally, the work is promising as it can be used to treat various diseases, such as arthritis and atherosclerosis, where this particular monocyte subset is implicated directly.
The entry of nanoparticles to the human body is most likely to occur through the blood circulatory system. Therefore, it becomes important to fully understand the effect of the blood protein adsorption onto nanoparticles and the influence of nanoparticles on the aptness of coated nanoparticles, that later interact with other biological interfaces, which in the long run develop biological effects such as cellular responses. There are interaction processes linking SWNTs and proteins of the human blood cells, including immunoglobulin, transferrin, fibrinogen, and albumin. The thermodynamic equilibrium is realized after about 10 minutes in BSA and Tf adsorption, while, on the other hand, Ig and BFG pack gradually onto the surface of SWNT for a considerable length of time, up to 5 h. The protein adsorption rate for various proteins are given in the following order: Ig has the highest rate, followed by BFG, and then BSA; while ferritin has the lowest rate of adsorption in the first five minutes but after the 5 minutes the order changes. Now BFG has the highest rate followed by Tf, and then BSA, while ferritin has the lowest rate before and after five minutes.
The recent researches in gene therapy, particularly the small interface RNA, suggest promising developments that may be applied for curing various diseases that are difficult to treat. However, the main challenge that still exists and hinders the therapy is how to deliver therapeutic nucleic acid without eliciting toxicity to targeted sites. The Trojan horse method is not possible for such an application because the selective uptake of SWNTs does not disqualify toxicity in the process. This is one of the major weaknesses of the work. Though the work is remarkable due to their needle-like shape their amazing optical and electronic properties, and the fact that, with further research, their large surface area may enable SWNTs to solve the toxicity problem.
The current study sets a basis for developing researches to solve the challenging transport problems. Main advantages that make SWNTs most applicable in medicine are their ability to enter the cells that are difficult to penetrate using traditional delivery mechanisms, they can penetrate bacteria and primary-immune cells, which are difficult to transfect. Such ability is provided by electrical properties, hydrophobic surface, and a needle-like shape. There is the capacity to achieve temporally-and spatially- managed discharge of silencing targeted genes, owing to their adsorption strength in the near infrared range. Their noteworthy flexibility, unique shape, and modifiable surface chemical properties have an influence on the conformation transition of siRNA/DNA. Lastly, their ability to timely monitor the effects of siRNA/DNA in therapeutic effect; the ability is brought about by their strong Raman signal, extreme stability, and near infrared fluorescence emission.
In this work, the authors have not thoroughly explained the time period required for the thermal balance/thermal equilibrium (time when there is no more change in heat transfer from one point to another, marking end of the process) in the interaction process for different protein coated SWNTs . The thermodynamic equilibrium is a critical parameter because it determines the rate of adsorption of proteins. From the study, it is seen that toxicity is enhanced by the type of protein coating in the SWNTs; thus, understanding the principle behind the thermodynamic equilibrium of various SWNTs protein coating, it is easier to overcome toxicity with further research.
There are notable findings in the write-up. The work identifies and establishes that SWNTs target one most important monocyte subset in the blood, and also that RGD ligands bonded to SWNTs can be utilized to intensify the cell delivery into sites of the tumor, effectively ‘conditioning’ them to get into the interstitium of the tumor. This is a huge goal despite the fact that the toxicity issue is still unsolved. The main reason as to why toxicity has not been overcome could be because the operation mechanism through which SWNTs monocytes are selected to Ly-6Chi remain unclear as well as the high frequency of targeting monocytes through RGD to the tumor is not sufficiently understood. By understanding the above mechanisms the researchers could help to eradicate toxicity in cancer treatment in the future.
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