A Review On Dendrimers: Nanoscale Marvels With Multifaceted Applications

Abstract

This Review Article focuses on the multifaceted applications of dendrimers and nanoscale marvels with unique, highly branched, star-shaped structures. This review covers the well-known applications of dendrimers as drug delivery systems and explores other potential uses in various fields. The unique properties of dendrimers, such as their well-defined three-dimensional architecture, nanoscale size, and multivalency, allow them to be utilized in a variety of applications, ranging from nanotechnology to biomedicine. This review also discusses the synthesis and functionalization of dendrimers, providing a comprehensive understanding of these nanoscale marvels. The aim was to highlight the versatility of dendrimers and their potential to revolutionize various fields with multifaceted applications. Dendrimers are highly branched, star-shaped macromolecules with nanoscale dimensions. They are characterized by their monodisperse structure, size control, and many functionalized terminal groups. These unique properties make dendrimers popular in the nanoscale world. They have been widely studied and applied in various fields such as Drug Delivery, Diagnostics, Catalysis, Material Science, Biomedical Applications, and sensor technology. Their ability to interact with various substances makes them useful for the development of sensitive and selective sensors.

Keywords

Novel, Nanotechnology, Lipophilic Drugs, Drug Delivery, Dendrimers & Multifaceted Applications.

Introduction

Dendrimers, first introduced by Fritz Vögtle in 1978 and later named by Donald Tomalia et al., are a unique class of synthetic polymers characterized by their highly branched, tree-like structure. Unlike linear and cross-linked polymers, dendrimers possess a high degree of molecular uniformity, a narrow molecular weight distribution, specific size and shape characteristics, and a highly functionalizable surface. These unique properties have made dendrimers a subject of intense research interest, with applications spanning materials science, nanotechnology[1], and biomedicine. This article will delve into the fascinating world of dendrimers and explore their history, synthesis, properties, and applications.

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    Figure 1 Dendrimer: A Basic View; by Nanoformulations in Human Health Conditions: The Paradigm Shift Vikas Pandey and Seema Kohli

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History:

Dendrimers[2], a class of synthetic polymers, have a unique, highly branched structure that sets them apart from linear and cross-linked polymers. The history of dendrimers is fascinating and dates back to the mid-20th century when Fritz Vögtle and his team first reported on cascade molecules. However, the term "dendrimer" was not coined until 1978 by Donald Tomalia and his team at Dow Chemical Company. They synthesized the first full-generation dendrimer, poly(amidoamine) (PAMAM) dendrimer. In subsequent years, the field of dendrimer research expanded rapidly. In the 1980s, Majoral and his team developed phosphorus-based dendrimers and George R. Newkome introduced the term "arborols" for dendritic macromolecules. In the 1990s, the potential of dendrimers in various applications was realized. For example, the first dendrimer-based drug delivery system was reported in 1995. The 2000s saw further advancements in the field, including the development of more complex dendrimer structures and the exploration of their use in nanotechnology[3], biomedicine, and other fields. Dendrimer research continues to be a vibrant and evolving field, with ongoing studies on their synthesis, properties, and applications. 

Dendrimer vs Other Novel Drug Delivery System-

Dendrimers[4,5] offer several advantages over other novel drug delivery systems, owing to their unique properties. They have a well-defined, compact, and globular three-dimensional architecture, and their size and surface functionality can be precisely controlled. This allows the tailoring of dendrimers to carry specific drugs and target specific cells or tissues in the body. Dendrimers can encapsulate drug molecules within their interior or attach them to their surfaces, thereby providing a high drug-loading capacity[6]. Surface groups can also be modified to improve solubility, enhance cellular uptake, or prevent rapid clearance from the body, thereby improving drug bioavailability and efficacy. Additionally, the nanoscale size of dendrimers allows them to bypass biological barriers and reach the targeted sites more effectively. They can also potentially reduce the toxicity of certain drugs by encapsulating them and releasing them only at the targeted site, thereby minimizing their exposure to healthy tissues. Moreover, dendrimers can be engineered to have a controlled release profile The controlled release profile of dendrimers allows them to release the drug over a sustained period, which can improve patient compliance and therapeutic outcomes. Furthermore, the well-defined and versatile nature of dendrimers allows the attachment of various functional groups, making them suitable for multifunctional drug delivery systems. For example, targeting ligands can be attached to the dendrimer surface to guide the nanocarrier to specific cells or tissues, imaging agents can be incorporated for diagnostic purposes, and other therapeutic agents can be co-delivered for combination therapy. Compared to other novel drug delivery systems such as liposomes, nanoparticles, or micelles, dendrimers offer several advantages. For instance, dendrimers have higher stability than liposomes and can encapsulate both hydrophilic and hydrophobic drugs. Compared to nanoparticles, dendrimers have a more defined and controllable size and structure, which can lead to more predictable and reproducible behavior in biological systems. However, it is important to note that although dendrimers offer significant potential as drug delivery systems, there are still challenges to be addressed. These include potential toxicity issues, complexity and cost of synthesizing dendrimers, and need for controlled and targeted drug release. Moreover, the choice between dendrimers and other drug delivery systems depends on the specific requirements of the drug to be delivered, such as its chemical properties, target site, and the desired release profile. 

Composition of Dendrimer-

The composition of dendrimers is unique and complex. Dendrimers are typically composed of three major parts: 

1. Central Core:

The central core is the starting point of the dendrimer. It is usually a multifunctional molecule that can initiate the growth of branches. The nature of the core can influence the properties of the dendrimer such as its size, shape, and reactivity. 

2. Interior Layers (generations):

Interior layers or generations of a dendrimer are formed by repeated branching from the central core. Each new layer is called a 'generation' and significantly increases the dendrimer size and number of surface functional groups. These interior layers can encapsulate guest molecules, making dendrimers useful for applications, such as drug delivery. 

3. Surface Functional Groups:

The surface of the dendrimer is covered with functional groups. These groups can be tailored during the dendrimer synthesis to achieve specific properties. They play a crucial role in determining the solubility, reactivity, and other properties of the dendrimers. Moreover, these functional groups can interact with other molecules, making dendrimers useful in various applications such as catalysis and sensing.  The composition of dendrimers is a complex and highly customizable aspect of nanoscale marvels. This allows a wide range of applications and functionalities.

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    Figure 2 Dendrimer Structure Overview

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Dendrimers in Drug Delivery[7][8]-

Dendrimers are promising tools in the field of drug delivery owing to their unique properties, such as their highly branched nanoscale structure and ability to control their size and surface functionality. Drugs can be encapsulated within a dendrimer or attached to its surface. This allows for a high drug loading capacity and the possibility of modifying the dendrimer surface to improve solubility, enhance cellular uptake, or prevent rapid clearance from the body. This can improve the bioavailability and efficacy of the drugs. Drugs that have been successfully encapsulated in dendrimers include anti-inflammatory, anti-cancer, antibiotic, and antiviral drugs. For instance, dendrimers have been used to deliver the anticancer drug methotrexate, with studies showing enhanced efficacy and reduced toxicity compared with free methotrexate. In addition, dendrimers have also been used to encapsulate antiinflammatory drugs, such as ibuprofen and indomethacin, improving their solubility and bioavailability[9]. Antibiotics such as vancomycin have also been encapsulated in dendrimers to enhance their antibacterial activity. In the case of antiviral drugs, dendrimers have been used to deliver anti-HIV drugs, such as zidovudine and efavirenz, showing promising results in terms of increased efficacy and reduced side effects. However, although the encapsulation of drugs in dendrimers has shown promising results in laboratory and animal studies, more research is needed to determine their safety and effectiveness in humans. Some challenges that need to be addressed include potential toxicity, the complexity and cost of dendrimer synthesis, and the need for controlled and targeted drug release. Overall, dendrimers represent a promising approach for drug delivery, with the potential to improve the effectiveness and safety of a wide range of medications.   Dendrimers offer a promising platform for drugs[10] and we anticipate that dendrimers will play a crucial role in the future of drug delivery. Their unique properties, such as high drug-loading capacity, ability to bypass biological barriers, and potential for targeted and controlled drug release, make them an attractive platform for the delivery of a wide range of therapeutic agents. However, it is important to note that the use of dendrimers in drug delivery remains an active area of research. At the same time, laboratory and animal studies have shown promising results, and more research delivery, with the potential to improve the efficacy, safety, and patient acceptability of various therapeutic agents. They represent a significant step forward in the development of targeted drug delivery systems, offering the potential to enhance the effectiveness of many different types of medications, including anti-inflammatory, anti-cancer, antibiotic, and antiviral drugs. As research continues in this field, we expect to see more innovative applications of dendrimers in drug delivery, potentially leading to more effective and safer treatments for a variety of health conditions.  They have a well-defined, compact, and globular three-dimensional architecture, and their size and surface functionality can be precisely controlled. This allows the tailoring of dendrimers to carry specific drugs and target specific cells or tissues in the body. Dendrimers can encapsulate drug molecules within their interiors or attach them to their surfaces, providing a high drug-loading capacity. Surface groups can also be modified to improve solubility, enhance cellular uptake, or prevent rapid clearance from the body, thereby improving drug bioavailability and efficacy. Additionally, the nanoscale size of dendrimers allows them to bypass biological barriers and reach the targeted sites more effectively. They can also potentially reduce the toxicity of certain drugs by encapsulating them and releasing them only at the targeted site, thereby minimizing their exposure to healthy tissues. Moreover, dendrimers can be engineered to have a controlled release profile to release the drug over a sustained period, which can improve patient compliance and therapeutic outcomes. 

Dendrimer vs Lipophilic Drugs-

Dendrimers are promising tools for the delivery of lipophilic drugs. Lipophilic drugs are soluble in lipids and often face challenges in drug delivery owing to their poor water solubility. This can lead to low bioavailability, which is the proportion of the drug that enters circulation when introduced into the body and can have an active effect. Dendrimers can overcome these challenges owing to their unique properties. They have a well-defined, compact, and globular three-dimensional architecture, and their size and surface functionality can be precisely controlled. This allows the tailoring of dendrimers to carry specific drugs and target specific cells or tissues in the body. Dendrimers can encapsulate lipophilic drugs within their interior or attach them to their surfaces, providing a high drug-loading capacity. The surface groups of the dendrimer can also be modified to improve solubility, which is particularly beneficial for lipophilic drugs. By encapsulating the lipophilic drug within the dendrimer, the drug can be dissolved in an aqueous environment inside the dendrimer, thereby improving its solubility and bioavailability. Furthermore, the nanoscale size of dendrimers allows them to bypass biological barriers and reach the targeted sites more effectively. They can also potentially reduce the toxicity of certain drugs by encapsulating them and releasing them only at the targeted site, thereby minimizing their exposure to healthy tissues. Moreover, dendrimers can be engineered to have a controlled release profile, thereby releasing the drug over a sustained period. This can be particularly beneficial for lipophilic drugs, which often require sustained release to maintain the therapeutic drug levels in the body. However, it's important to note that while dendrimers offer significant potential for the delivery of lipophilic drugs, there are still challenges to be addressed. These include potential toxicity issues, complexity and cost of synthesizing dendrimers, and need for controlled and targeted drug release. In conclusion, dendrimers, owing to their unique properties and versatility, represent a promising platform for the delivery of lipophilic drugs. They can improve the solubility and bioavailability of drugs, potentially enhance their efficacy, and reduce their toxicity. As research continues in this field, we expect to see more innovative applications of dendrimers in drug delivery, potentially leading to more effective and safer treatments for a variety of health conditions. However, it is important to note that the use of dendrimers for the delivery of lipophilic drugs is still an active area of research, and more studies are needed to fully understand their behavior in biological systems and address any potential toxicity issues. Nonetheless, owing to their unique properties and versatility, dendrimers hold great promise in advancing the field of drug delivery and ultimately improving patient outcomes. These represent a significant step forward in the development of targeted drug delivery systems, offering the potential to enhance the effectiveness of many different types of medications, including lipophilic drugs. As we continue to explore and refine this technology, we will likely see more innovative and effective uses for dendrimers in the future.

Method of Formulation –

The preparation of dendrimers involves a series of chemical reactions that result in a highly branched, three-dimensional structure. This process can be broadly divided into two approaches: 

1. Divergent Method:

This method was first introduced by Tomalia and involves outward growth from a multifunctional core. The synthesis begins with a multifunctional core molecule. Each functional group on the core molecule reacts with a molecule that has one reactive group and two dormant groups. This has resulted in a new generation of branches. The process is repeated, with each cycle adding a new generation of branches, until the desired size and complexity are achieved. However, the divergent method can lead to structural imperfections, particularly as the dendrimer size increases, owing to incomplete reactions at each stage. 

2. Convergent Method:

This method was developed by Hawker and Fréchet to overcome the limitations of the divergent method. This involves the synthesis of dendrimer branches (dendrons), which are then attached to a multifunctional core. The advantage of this method is that it allows better control over the size and shape of the dendrimer, leading to more uniform and defect-free structures. However, the convergent method can be complex and time-consuming, particularly for larger dendrimers, because of the need to protect and deprotect the functional groups at each stage. 

In addition to these methods, other techniques, such as the double exponential growth method and click chemistry method, have also been developed to synthesize dendrimers. The choice of method depends on factors such as the desired size and structure of the dendrimer, type of monomers used, and intended application of the dendrimer. For instance, the double exponential growth method combines aspects of both divergent and convergent methods to accelerate the synthesis process and produce large dendrimers with fewer defects. The click chemistry method, on the other hand, uses highly efficient and selective reactions to join smaller dendrimers together, allowing for the rapid and precise construction of complex dendrimer structures. The preparation of dendrimers involves a series of complex chemical reactions, with different methods offering various advantages and challenges. The choice of the method depends on various factors, including the desired properties of the final dendrimer product and its intended application. Despite the complexity of these processes, the unique properties and potential applications of dendrimers render them a worthwhile area of study in materials science and nanotechnology. As research continues in this field, we expect to see further advancements in dendrimer synthesis methods, potentially leading to more efficient and costeffective processes. This, in turn, could expand the range of possible applications of dendrimers in areas such as drug delivery, diagnostics, and materials science. However, it is important to note that the synthesis of dendrimers is a complex process that requires a high level of expertise and precision, and there are still challenges to overcome, such as controlling the size and uniformity of the dendrimer, minimizing defects, and reducing the cost and complexity of the synthesis process. Nonetheless, with continued research and development, dendrimers hold promise for advancing the field of nanotechnology and for contributing to the development of novel materials and therapies.

Application of Dendrimer[11,12] – 

Dendrimers offer a versatile platform for drug delivery with the potential to improve the efficacy, safety, and patient acceptability of various therapeutic agents. They can be tailored to carry specific drugs, target specific cells or tissues, and release drugs over a sustained period. They can also be used to co-deliver multiple therapeutic agents, enhance the solubility of hydrophobic drugs, and to deliver imaging agents for diagnostic purposes.

1. Cancer Treatment:

Dendrimers can be used to deliver anti-cancer drugs directly to tumor cells, reducing the exposure of healthy cells to the drug and potentially reducing side effects. For example, dendrimers have been used to deliver the anticancer drug methotrexate, with studies showing enhanced efficacy and reduced toxicity compared with free methotrexate. 

2. Anti-inflammatory Drugs:

Encapsulation of anti-inflammatory drugs within dendrimers can enhance drug solubility, stability, and bioavailability. Additionally, they can protect the drug from premature degradation, provide controlled release, and potentially reduce side effects by targeting the drug to specific cells or tissues. Dendrimers can also be functionalized with specific ligands to enhance their targeting capability. Anti-inflammatory drugs such as ibuprofen and indomethacin improve their solubility and bioavailability. 

3. Antibiotics:

Dendrimers have been explored as potential carriers of antibiotics owing to their unique properties. Their well-defined, three-dimensional architecture and nanoscale size make them ideal for encapsulating antibiotics, thereby improving their delivery and effectiveness. The encapsulation of antibiotics within dendrimers can enhance their solubility and stability, protect them from degradation, and allow for controlled release. Moreover, dendrimers can be functionalized to target specific cells or tissues, thereby enhancing the specificity and reducing the side effects of antibiotics. However, challenges such as potential toxicity and the need for precise control over the encapsulation and release of antibiotics must be addressed. Antibiotics, such as vancomycin, have been encapsulated in dendrimers to enhance their antibacterial activity. 

4. Antiviral Drugs:

In the case of antiviral drugs, dendrimers have been used to deliver antiHIV drugs, such as zidovudine and efavirenz, showing promising results in terms of increased efficacy and reduced side effects. 

5. Gene Delivery:

Dendrimers have been explored for gene delivery applications. They can bind to DNA or RNA molecules and protect them from degradation, thereby facilitating their delivery to target cells. 

6. Imaging:

Dendrimers can be used to deliver contrast agents for imaging techniques such as MRI. Their ability to target specific tissues can improve the quality of images and potentially aid in disease diagnosis. 

7. Targeted Drug Delivery:

 Dendrimers can be engineered to target specific cells or tissues in the body, thereby improving the effectiveness of the drug and reducing side effects. This can be particularly useful in the treatment of diseases like cancer, where it's important to target the tumor cells specifically while sparing healthy cells.[13] 

8. Co-Delivery of Drugs:

Dendrimers can be used to co-deliver multiple therapeutic agents. This can be particularly useful in combination therapies in which two or more drugs are used together to enhance their therapeutic effect or to overcome drug resistance. For instance, in cancer treatment, a dendrimer can be used to co-deliver a chemotherapy drug and a gene therapy agent, potentially enhancing the effectiveness of the treatment. 

9. Enhanced Solubility:

Dendrimers can enhance the solubility of hydrophobic drugs and improve their bioavailability and efficacy. This is particularly useful for drugs with poor water solubility such as anticancer and anti-inflammatory drugs.

10. Controlled Release:

Dendrimers can be engineered to release their drug loads over a sustained period. This can improve patient compliance and therapeutic outcomes, particularly for drugs that need to be taken frequently or have a narrow therapeutic window. 

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    Figure 3 Diagrammatic representation of siRNA loading and unloading by dendrimer (Liu et al. 2014)

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However, it is important to note that while the potential of dendrimers is significant, more research is needed to fully understand their behavior in biological systems and address any potential toxicity issues. In addition, the process of designing and synthesizing dendrimers with desired properties can be complex and costly, which may pose challenges for their widespread use in drug delivery. Nonetheless, with continued research and development, dendrimers hold promise in advancing the field of drug delivery and ultimately improving patient outcomes. These represent a significant step forward in the development of targeted drug delivery systems, offering the potential to enhance the effectiveness of many different types of medications, from cancer treatments to antibiotics. As we continue to explore and refine this technology, we will likely see more innovative and effective uses for dendrimers in the future. For instance, we could see dendrimers being used to deliver a wider range of drugs, including new types of therapeutic agents that are currently being developed. We could also see improvements in the design and synthesis of dendrimers, making them more effective and easier to produce. Furthermore, as we gain a better understanding of the behavior of dendrimers in biological systems, we could see advances in the way they are used to target specific cells or tissues, potentially leading to more targeted and effective treatments for a variety of diseases. In addition, dendrimers could also be used in combination with other types of nanomaterials to create multifunctional drug delivery systems. For example, dendrimers could be combined with liposomes or nanoparticles to enhance their drug-loading capacity or to deliver multiple therapeutic agents simultaneously. 

Characterization Parameters for Dendrimer-Based Drug Delivery System-

The characterization parameters for dendrimer-based drug delivery systems can be broadly categorized into :

1. Physical Parameters:

These include size, shape, surface charge, and morphology of the dendrimer. Techniques such as Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) can be used to characterize these parameters. The size and shape of the dendrimer can influence its drug-loading capacity, cellular uptake, and biodistribution. The surface charge can affect its interaction with biological membranes and its stability in biological fluids. 

2. Chemical Parameters:

These include the type and number of surface groups, the type of core, and the type and number of branches. Techniques such as Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), and Mass Spectrometry (MS) can be used to characterize these parameters. The chemical properties of the dendrimer can influence its solubility, drug-loading capacity, and release behavior. For instance, the type and number of surface groups can be modified to improve the solubility of hydrophobic drugs or to attach targeting ligands for specific cells or tissues.

3. Biological Parameters:

These include biocompatibility, toxicity, immunogenicity, and biodistribution. Techniques such as cell culture studies, animal studies, and in some cases, clinical trials, can be used to characterize these parameters. The biological properties of the dendrimer can influence its safety and effectiveness as a drug delivery system. For instance, the dendrimer should be biocompatible and non-toxic to be safe for use in the body. Its immunogenicity, or its ability to provoke an immune response, should be minimal to avoid unwanted side effects. The biodistribution, or the distribution of the dendrimer in the body, can affect its ability to reach the target site and its clearance from the body.

4. Drug Loading:

The drug loading capacity of a dendrimer refers to the amount of drug that can be encapsulated within or attached to the dendrimer. This can be characterized by techniques such as UV-visible spectroscopy, High-Performance Liquid Chromatography (HPLC), or Mass Spectrometry (MS). The drug loading capacity can influence the dose of the drug that can be delivered and the duration of drug release. 

5. Drug Release Behavior:

This refers to the rate and pattern of the drug release from the dendrimer. Techniques such as dialysis, dissolution testing, or HPLC can be used to characterize the drug release behavior. The drug release behavior can influence the therapeutic effect of the drug and the duration of its action. For instance, the drug can be released in a controlled manner over a sustained period, which can improve patient compliance and therapeutic outcomes. 

6. Stability:

The stability of the dendrimer in various environments (such as different pH levels, temperatures, or biological fluids) can be characterized by techniques such as DLS, HPLC, or stability studies under different conditions. The stability can influence the dendrimer-based drug delivery system's shelf-life, its body behavior, and its ability to retain the drug until it reaches the target site.   The characterization of dendrimer-based drug delivery systems involves a comprehensive evaluation of their physical, chemical, and biological properties, as well as their drug loading and release behavior, and stability. These parameters can influence the performance of the dendrimer as a drug delivery system, including its ability to carry and release the drug, its interaction with biological systems, and its safety. Therefore, it's important to thoroughly characterize these parameters to optimize the design of the dendrimer for its intended application. 

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    Figure 4 A Lookout overview of Dendrimer

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CONCLUSION-

The significant potential of dendrimers is due to their unique properties such as well-defined, three-dimensional architecture, nanoscale size, and multivalency. These properties make them ideal for a variety of applications, not only in drug delivery systems but also in other fields such as nanotechnology and biomedicine. The review also highlights the importance of understanding the synthesis and functionalization of dendrimers for their effective use in these applications. It is concluded that dendrimers, with their versatility and multifaceted applications, have the potential to revolutionize various fields. Future research should focus on overcoming the challenges associated with their use and exploring new avenues for their application. 

SUMMARY-

Dendrimers are nanoscale, star-shaped macromolecules with unique properties that make them ideal for a variety of applications. Their well-defined, three-dimensional architecture, nanoscale size, and multivalency enable them to be used in drug delivery systems and other fields such as nanotechnology and biomedicine. The discussion also covered the synthesis and functionalization of dendrimers, providing a comprehensive understanding of these nanoscale marvels. The review aimed to highlight the versatility of dendrimers and their potential to revolutionize various fields with their multifaceted applications. This summary provides a snapshot of the in-depth exploration of dendrimers, their properties, and their wide-ranging applications. 

FUTURE RESEARCH IN DENDRIMERS -

One should focus on exploring and expanding the potential applications of dendrimers in various fields. Given their unique properties such as well-defined, three-dimensional architecture, nanoscale size, and multivalency, dendrimers can revolutionize drug delivery systems and other areas such as nanotechnology and biomedicine. One of the key areas of future research should be the development and refinement of synthesis and functionalization techniques for dendrimers. This will allow for more precise control over their properties, which in turn could open up new avenues for their application. Future research should also address the potential challenges associated with the use of dendrimers, such as toxicity and biocompatibility issues. By addressing these challenges, we can fully harness the potential of these nanoscale marvels and their multifaceted applications.

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