Introduction
Peptides play an important role in regulating the functional activities of various systems, organs, tissues and cells in the body and life activities, and are often used in disease research, cosmetics, drug research and development and other fields. Peptides can be divided into cyclic and linear peptides according to whether they are cyclic or not. The synthesis technology of linear peptides is very mature. The synthesis of linear peptides consisting of hundreds of Amino Acid has been achieved. Although many linear peptides have good biological activity and stability in vitro, the linear peptides are degraded under the action of enzymes after entering the body, which eventually leads to the loss of their activity.
With the deepening of the understanding of life phenomena and protein functions and the expansion of the demand for lead compounds and various functional materials for drug design, people pay more attention to peptides with special structures and special properties. Among a wide variety of peptide compounds, cyclic peptides are an extremely important one. Cyclic peptides have a well-defined fixed conformation, are more rigid than linear peptides, and exhibit stronger affinity for target receptors. In addition, the absence of free amino and carboxyl groups in the cyclic peptide molecule greatly reduces its sensitivity to enzymes. The special structure of cyclic peptides and the stability to enzymatic degradation make them widely used in biomedicine, medicine, nanomaterials, supramolecular self-assembly and other fields.
Cyclization is the most direct way to synthesize cyclic peptides, especially for peptides with larger structural backbones. Generally, the cyclization of peptides containing 7 or more amino acids is relatively smooth, and the cyclization of peptides containing less than 7 amino acids is difficult.
Commonly Used Cyclization Methods
According to the cyclization method of cyclic peptides, it can be divided into side chain-to-side chain type, head-to-tail type, side chain-to-end type, and disulfide-bridge.
(1) Side chain-to-side chain
This cyclization method involves the formation of amide structures between aspartic acid or glutamic acid residues and the base amino acid. Side chain protecting groups must be selectively removable, whether the peptide is on resin or after dissociation. In addition, this cyclization method can also form diphenyl ethers via tyrosine or p-hydroxyphenylglycine.
(2) Disulfide-bridge
This cyclization was introduced by deprotection of a pair of cysteine residues followed by oxidation to form a disulfide bond. The synthesis of multiple rings can be achieved by selectively removing the thiol-protecting group. Cyclization can be done either in the solvent after dissociation or on the resin before dissociation.
(3) Side chain-to-end
This cyclization method typically involves the C-terminus of a linear peptide with the amino group of a lysine or ornithine side chain, or the N-terminus of a linear peptide with a carboxyl group of an aspartic acid or glutamic acid side chain. In addition, this cyclization method also involves the formation of ether bonds between the C-terminus of linear peptides and the side chains of serine or threonine.
(4) Head-to-tail
End-to-end cyclic peptides are usually condensed into a ring by the N-terminal amino group and C-terminal carboxyl group of the linear peptide. The type and number of amino acids in linear peptides play a crucial role in the ease of cyclization and the yield of cyclic peptides. Linear peptides can be cyclized in a solvent or immobilized on a resin by side chain cyclization.
FDA-Approved Cyclic Peptide Drugs
In the future, some applications of cyclic peptides in the pharmaceutical industry are expected to surpass small molecules and antibodies.
The following are cyclic peptides approved for clinical use between 2001 and 2021:
Cyclic peptide drugs targeting intracellular proteins
Other Cyclic Peptide Products
Cyclic peptides are attracting more and more attention as a unique molecular class.
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When parts or the whole of certain tissues or organs fail, there are several options for treatment, including repair, replacement with a synthetic or natural substitute, or regeneration. The fabrication of a cell scaffold with hydrogel derived from natural polymer materials is an attractive method to be applied for tissue engineering, but some undesirable mechanical properties and immunogenic risks of natural hydrogel are a dilemma for this kind of application. However, PEG is a promising raw material for biomaterials as well as for tissue engineering.
Advantages
There are several advantages of PEG as the raw materials for tissue engineering among other natural materials.
Synthetic Versatility
PEG that synthesized via anionic polymerization of ethylene oxide, is a synthetic and non-biodegradable polymer that can be dissolved in water with any length. Therefore, the polymerization of PEG from ethylene oxide or ethylene glycol is easily controllable in aqueous solutions with quite narrow polydispersity. Linear PEG bears only two functional groups at the end of its chain, and commercial PEGs are available with different molecular weight and functionality. While multi-arms PEG derivatives can be prepared by ethoxylation of different cores such as pentaerythritol, hexaglycerol, or tripentaerythritol. With the versatility of PEG raw materials on the market, various PEG-based products can be manufactured for the tissue engineering applications.
Biocompatibility and Biodegradability
The biocompatibility of PEG was intensive investigated but many researchers, and all of them prove this result, and demonstrate the potential application as the cell scaffold in tissue engineering. While the PEG itself has the resistance to protein adsorption, which limits the biodegradation of PEG scaffold in tissue, the block copolymer of PEG with many biodegradable polymers, such as polylactic (PLA) and polycaprolactone (PCL), can yield a new generation of PEG copolymer that inherently possesses the biocompatibility and biodegradability. Moreover, the degradation degree can be controlled by choosing vast types of PEG copolymer.
Tunable Structure
In addition to its chemical composition, the mechanical properties of PEG-based scaffold can also be tuned. Stiffness, porosity, mechanical stability and elasticity are the properties that very crucial to evaluate the biomaterials as well as the cell scaffolds. These properties are largely correlated to the degree of crosslinking. Not only the length and the molecular weight of PEG can be manipulated during the synthesis procedures, but also the functionality of end groups can be chemically modified. At meanwhile, the types of active chemicals that react with PEG to fabricate the hydrogel or scaffold is variable. All these parameters are related to the crosslinking density that influences the mechanical properties. To be used as scaffold for tissue engineering applications, the material must provide an optimal niche for cell proliferation and differentiation, focused on cell attachment. Therefore, the modifications are used to tune this property. Overall, the tunable structure of PEG hydrogel endows assorted possibilities to it on the application of tissue engineering.
Preparation methods of PEG hydrogel for scaffold
Michael addition
The Michael addition is a facile reaction between nucleophiles and activated olefins and alkynes. The mild reaction condition, the rapid cure and high conversions under physiological environment are of great significance for biological applications such as the incorporation of bioactive macromolecules and cells.
Click Chemistry
This click reaction is highly chemo-selective and can be performed under mild conditions in aqueous buffers with a wide range of pH, indicating high applicability for site-specific reaction, and generally results in a high yield of the desired product. The crosslinking in these hydrogels is extremely high, and results in a more ideal structure leading to improved properties when compared to traditional photochemically-crosslinked PEG hydrogels.
Enzymatic Reaction
Most enzymes catalyze chemical reactions at low temperature, neutral pH, and in buffered aqueous solutions, mild conditions under which many conventional chemical reactions fail. Enzymes can also be exceptionally selective for their substrates, allowing for sophisticated, biologically inspired designs without the complication of side-reactions and cellular toxicity.
Photopolymerization
The most common approach to make PEG hydrogels is photopolymerization, which utilizes light to convert liquid PEG macromer solutions into solid hydrogels at physiological temperature and pH. This method is advantageous for fabricating hydrogel scaffolds in situ with spatial and temporal control and in a variety of 3D structures with encapsulation of cells and biological agents. PEG acrylates are the major type of macromers used for photopolymerization, including PEG diacrylate (PEGDA), PEG dimethacrylate (PEGDMA), and multiarm PEG (n-PEG) acyrlate (n-PEG-Acr).
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Over the years, the absolute quantification (AQUA), based on isotope-labeled peptides has become a resultful means of quantifying proteins. AQUA can quantitatively study various complicated biological samples and provide valuable new tools for proteomics.
Properties of AQUA Peptides
The target peptides of the protein to be quantified should be able to ionize effectively and be easily detected by mass spectrometry (MS).
The target peptides should avoid containing methionine and cysteine and other sites that are prone to chemical modification.
The target peptides should not contain special sequences such as the aspartic acid-glycine that is easily broken by enzymatic cleavage.
The target peptides should avoid bearing or near post-translational modification sites.
The length of the peptide should be controlled within 7-20 amino acids as much as possible, in order to obtain a better MS signal.
Experimental Method
The hydrolyzed peptides of the target protein are obtained by experimental or predictive methods. A certain amount of isotopic label was added to the analysis sample as a reference to reduce quantitative differences caused by matrix effects, ionization efficiency and unstable instrument response signals during the experiment. The isotope-labeled peptides are incorporated into cell lysates at known concentrations by proteolysis. The isotope-labeled peptide and the tested peptide show the same physical and chemical properties and different mass-to-charge ratios. Therefore, the target protein of the sample is calculated by the ratio of the labeled/unlabeled peptide and the absolute amount of the labeled peptide.
Advantages
AQUA technology can accurately and sensitively detect proteins with medium and high abundance in various samples and under various conditions, and requires trace amounts of samples. AQUA peptides can be incorporated proportionally when quantifying a set of proteins with a wide dynamic range. AQUA peptides are readily available and simple to use, enabling comparability of quantitative data from different laboratories and different instruments. Besides, AQUA can also be applied for absolute quantification of post-translationally modified proteins, such as phosphorylation modification, using each of the unmodified/phosphorylated AQUA peptides as the reference to quantify the total protein expression and the occurrence of phosphorylation protein abundance.
Technology applications
Through the high-throughput screening of proteomics, combined with AQUA-based and Multiple Reaction Monitoring (MRM) / Parallel Reaction Monitoring (PRM)/ Selected Reaction Monitoring (SRM) technology to verify in large-scale samples, it is found that the diagnostic markers of protein diseases are better than the traditional alpha-fetoprotein (AFP) and glycoproteins. The combination of markers (Apolipoprotein H, Orosomucoid 2 (ORM 2), and AFP was more accurate in the diagnosis of liver cancer. The mass spectrometry-based AQUA strategy has also been used in subunit studies of protein complexes to detect the levels of different subunits in serum. The AQUA strategy can also be utilized for quantifying low-abundance proteins involved in gene silencing and quantitatively identifying the cell cycle-dependent phosphorylation of proteins. Furthermore, AQUA is also applicable to the external standard curve method. Compared with the traditional single-point quantitative method, the external standard curve method can take into account the differences in protein concentration of multiple orders of magnitude, and is suitable for the detection of protein quantitative content in large-scale samples with a large dynamic range.
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What are exosomes?
Exosome is a type of extracellular vesicle (EV) with a diameter of about 30-150 nm. They are secreted by all cell types and can be found in most body fluids, including blood, saliva, and urine. Exosomes are "nanospheres" with bilayer membranes, which contain a wide array of substances from parent cells, such as microRNAs, mRNA expression, lncRNA, DNA, lipids, peptides, and proteins (including oncoprotein, Tumor suppressor genes, transcription regulators and splicing factors). The composition of exosomes is critical because they can be used as biomarkers and provide an indication of their function in biological processes.
Functions of exosomes
Depending on the source of the exosomes, they have different functions. Generally, the function of exosomes promotes intercellular communication throughout the body in a target-specific manner. Currently, exosomes are known to participate in many biological processes, including maturation of red blood cells, elimination of unnecessary proteins and RNA, antigen presentation in immune responses, coagulation, inflammation, and angiogenesis.
In addition to normal biological processes, exosomes have been found to be associated with many common diseases, such as cancer, neurodegenerative diseases (Parkinson's disease, etc.), myocardial infarction, and AIDS.
Given that exosomes can be isolated from almost any cell, participate in intercellular communication, and participate in normal and pathobiological mechanisms, exosomes are used as a diagnostic and therapeutic method in more and more studies.
How do exosomes exert biological effects?
Exosomes can exert their biological effects in a number of ways:
Exosome surface proteins or biologically active lipid ligands bind to surface receptors of recipient cells to regulate downstream signal transduction.
Fusion with the cell membrane of the recipient cell, and introduce functional content (transcription factors, oncogenes, regulatory non-coding RNA, mRNA, infectious molecules, etc.) into the recipient cell to regulate its function.
The recipient cell absorbs the exosomes through cytocytosis or phagocytosis, and the contents of the exosomes are released in the recipient cells, thereby affecting the function of the recipient cells.
How are exosomes used in drug development?
Intervention of disease-related exosomes
Exosomes can mediate the pathological processes of various diseases, and regulating disease-related exosomes can play a role in relieving or treating diseases. This can be achieved by interfering with the generation, release, uptake and functional contents of related exosomes.
Therapeutic exosomes as drugs
Because exosomes are rich in biologically active substances, they have a certain therapeutic potential. For example, stem cell-derived exosomes have the functions of promoting angiogenesis, inhibiting apoptosis, promoting cell proliferation, and releasing immunoregulatory substances, and have certain application value in the field of regenerative medicine.
Exosomes as delivery vehicles
Exosomes can carry signal molecules such as RNA, DNA, and proteins, so they can be used as therapeutic carriers for therapeutic macromolecules. For example, exosomes can be used as therapeutic carriers for therapeutic nucleic acid drugs, delivering mRNA, miRNA, etc. to target cells, thereby regulating the expression of target genes to play a therapeutic role. Compared with previous non-viral drug delivery vehicles, exosomes as drug delivery vehicles have higher biocompatibility and lower immunogenicity can be obtained from patient autologous cell culture and can pass the blood-brain barrier.
What are the advantages of exosomes as drugs?
Exosome therapy, as a new treatment method, brings some new opportunities for the current treatment of some refractory diseases or the development of drugs with difficult drug targets.
Stem cell-derived exosomes can also play a role in promoting cell regeneration or repair. In this way, it can play a role instead of stem cells, thereby avoiding the risk of immune infection and cancer caused by stem cell therapy.
The expression of tissue antigens on the surface of exosome membranes provides a biological basis for the development of organ, tissue or cell division drugs.
In addition, exosomes have low immunogenicity, do not cause adverse reactions in the immune system, can be repeated, and can pass non-invasively through many tissue barriers (such as blood-brain barrier, etc.).
Learn More about Our Ability of Exosome Drug delivery
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In the past few years, there has been a great interest in a class of promising drugs, which do not work by inhibiting the molecular target as most traditional drugs do, but use the cell recovery system to destroy the target. However, it is difficult to find and design such unusual compound drugs, which are collectively called the molecular glue degraders.
Now, a new molecular glue-degrading agent called CR8 was discovered by scientists at the Broad Institute in the United States and the Friedrich-Michel Biomedical Institute in Basselle, Switzerland. By dissecting the details of the molecular mechanisms of CR8, these researchers show the possibility of building more of these unique compounds as potential treatments for various diseases. The results of the study were recently published in Nature, entitled “The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K”.
“By attaching a specific chemical group, it is possible to convert conventional kinase inhibitors into molecular glue degradants, which provides the potential to build molecular glue degradants for a wider range of therapeutic targets than we initially expected.” wrote Benjamin Ebert, co-author of the article and a cancer researcher at the Broad Institute.
Throw away the lock-and-key theory
Most drugs use lock-and-key mechanisms to target proteins (usually enzymes), blocking their activity by binding directly to unique grooves on the target proteins. However, many other types of proteins, such as transcription factors, lack such binding sites, hampering efforts to design drugs for these traditionally “undruggable” targets.
About six years ago, Ebert and his colleagues revealed that a well-known multiple myeloma drug called lenalidomide works as a molecular glue-degrading agent. Instead of directly binding to the target, it works by recruiting a molecular machine to label the target protein in the cell so that it can be subsequently destroyed. The molecular machine, called E3 ubiquitin ligase, attaches a small protein called ubiquitin to an ill-fated target, which is then degraded by the cell recovery system.
To identify more molecular glue degradants, the Ebert team, led by co-lead author Mikolaj Slabicki, a postdoctoral fellow at the Broad Institute, studied data on more than 4500 drugs and compounds from the Broad Institute Drug Reuse Center, which has collected the data on compounds that had been proven to be safe for humans, especially many compounds that have been approved by the U.S. Food and Drug Administration (FDA). They combed through the public data to determine the priority of drugs that kill cancer cells with higher levels of E3 ubiquitin ligase.
“We have been brainstorming in the lab, trying to find more molecular glue degradants. We are very lucky to have such a large and powerful data set. we would not have made such a discovery without this data set generated by the Broad Institute Cancer Project. ” said Slabicki.
Ways to build more molecular glue degradants
CR8 is a compound originally designed to inhibit enzymes called cyclin-dependent kinase (CDK), which plays an important role in controlling cell growth. Using their bioinformatics methods, the researchers found that the cytotoxicity of CR8 is related to the level of a component called DDB1 in the E3 ubiquitin ligase complex.
The researchers found that CR8 kills cancer cells by inducing the degradation of a protein called cyclin K, which is the binding companion of some CDKs, especially CDK12. CR8 works like molecular glue. It binds to CDK12-cyclin K and recruits DDB1, and then recruits the rest of the E3 ubiquitin ligase complex to label cyclin K for subsequent degradation.
Researchers from the Bassel Friedrich-Michel Institute for Biomedical Research including Nicolas Thom, co-author of the paper, and co-lead authors Zuzanna Kozicka and Georg Petzold analyzed the crystal structure of the key components of the CR8-induced protein complex, revealing new molecular details of the interaction between all glued parts.
The group studied the activity of a drug with a structure similar to CR8 and found that it does not cause cyclin K degradation. The only structural difference between the two compounds is the protruding of a chemical group called pyridyl substituent. They concluded that the chemical group is enough to make CR8 act like a molecular glue degrader. This finding suggests that the extroverted parts of inhibitors can be chemically modified to be turned into molecular glue degradants targeting specific protein targets.
“Our findings suggest that we may be able to design these compounds ourselves, and there may also be many other molecular glue degradants, but they have not been discovered because the stability of their targets has not been studied. This is really exciting,” said Ebertd.
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December 27, 2023
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Introduction
Amino acids, vitamins, and minerals are essential substances for humans. Therefore, many foods add these substances to complete the body’s nutritional supplement. Amino acids, vitamins, and minerals are essential substances for human beings. Therefore, many foods add these substances to complete the body’s nutritional supplement. However, many amino acids, vitamins, and minerals are susceptible to oxidative denaturation or photolysis caused by external environmental influences such as light, temperature, or oxygen, and suffer great losses during food processing, thus failing to achieve the purpose of supplementing the body’s nutrition, which greatly limits their application in food. Embedding these substances can play a good role in protecting and reducing losses, in which embedding liposomes as the material is a great advantage.
Advantages
The ability of liposomes to encapsulate both lipophilic and hydrophilic substances, their degradability in living organisms, their good biocompatibility, and their relatively small size compared to other carriers means that they are easily and uniformly dispersed throughout the food interior. When wrapped in liposomes, the stability of amino acids, vitamins, and minerals is improved, losses during processing are reduced, and they are more easily absorbed by the human body, prolonging the effective shelf life of these substances and improving the quality of food by masking some abnormalities.
Examples
Vitamin C (ascorbic acid) is very unstable and can be easily oxidized during processing and storage. After preparation into liposomal microcapsules, the stability of vitamin C can be greatly enhanced. The effective vitamin C content of this liposomal product remains above 50% after 50 days of storage at 4°C, while all vitamin C in its free state is degraded after 20 days. In addition, liposomal capsules of vitamins may improve product stability to some extent even in the presence of degraded substances (e.g. copper, ascorbate oxidase, and lysine).
For vitamin D and vitamin A, liposome encapsulation also improved their stability. In a neutral environment and at 4°C, free vitamin A and vitamin A in the cache system are completely degraded within two days, while vitamin A after incorporation of liposome protection has only a 20% degradation rate after the eighth day, and the liposome protection is even more significant if stored away from light.
Liposome encapsulation technology can also protect minerals, such as calcium ions, magnesium ions, and iron salts. Calcium ions encapsulated by liposomes can avoid the coagulation effect of soy protein in soy milk production, and the calcium content in calcium-added soy milk even exceeds that of natural milk. Some producers encapsulate magnesium ions in liposomes to promote dietary nutritional balance. The direct addition of iron salts to dairy products produces a metallic odor and can cause lipid peroxidation and color changes, but encapsulation in liposomes can mask such changes and improve the quality of dairy products containing iron salts.
About Us
Liposome encapsulation is a necessary step in the preparation of liposome drugs. The cargo is usually loaded during this step, strongly influencing the packaging load. BOC Sciences liposome platform provides you with the best liposome encapsulation services. We can select specific phospholipids and techniques to prepare liposomes based on the cargo or the release conditions.
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What are exosomes?
Exosome is a type of extracellular vesicle (EV) with a diameter of about 30-150 nm. They are secreted by all cell types and can be found in most body fluids, including blood, saliva, and urine. Exosomes are "nanospheres" with bilayer membranes, which contain a wide array of substances from parent cells, such as microRNAs, mRNA expression, lncRNA, DNA, lipids, peptides, and proteins (including oncoprotein, Tumor suppressor genes, transcription regulators and splicing factors). The composition of exosomes is critical because they can be used as biomarkers and provide an indication of their function in biological processes.
Functions of exosomes
Depending on the source of the exosomes, they have different functions. Generally, the function of exosomes promotes intercellular communication throughout the body in a target-specific manner. Currently, exosomes are known to participate in many biological processes, including maturation of red blood cells, elimination of unnecessary proteins and RNA, antigen presentation in immune responses, coagulation, inflammation, and angiogenesis.
In addition to normal biological processes, exosomes have been found to be associated with many common diseases, such as cancer, neurodegenerative diseases (Parkinson's disease, etc.), myocardial infarction, and AIDS.
Given that exosomes can be isolated from almost any cell, participate in intercellular communication, and participate in normal and pathobiological mechanisms, exosomes are used as a diagnostic and therapeutic method in more and more studies.
How do exosomes exert biological effects?
Exosomes can exert their biological effects in a number of ways:
Exosome surface proteins or biologically active lipid ligands bind to surface receptors of recipient cells to regulate downstream signal transduction.
Fusion with the cell membrane of the recipient cell, and introduce functional content (transcription factors, oncogenes, regulatory non-coding RNA, mRNA, infectious molecules, etc.) into the recipient cell to regulate its function.
The recipient cell absorbs the exosomes through cytocytosis or phagocytosis, and the contents of the exosomes are released in the recipient cells, thereby affecting the function of the recipient cells.
How are exosomes used in drug development?
Intervention of disease-related exosomes
Exosomes can mediate the pathological processes of various diseases, and regulating disease-related exosomes can play a role in relieving or treating diseases. This can be achieved by interfering with the generation, release, uptake and functional contents of related exosomes.
Therapeutic exosomes as drugs
Because exosomes are rich in biologically active substances, they have a certain therapeutic potential. For example, stem cell-derived exosomes have the functions of promoting angiogenesis, inhibiting apoptosis, promoting cell proliferation, and releasing immunoregulatory substances, and have certain application value in the field of regenerative medicine.
Exosomes as delivery vehicles
Exosomes can carry signal molecules such as RNA, DNA, and proteins, so they can be used as therapeutic carriers for therapeutic macromolecules. For example, exosomes can be used as therapeutic carriers for therapeutic nucleic acid drugs, delivering mRNA, miRNA, etc. to target cells, thereby regulating the expression of target genes to play a therapeutic role. Compared with previous non-viral drug delivery vehicles, exosomes as drug delivery vehicles have higher biocompatibility and lower immunogenicity can be obtained from patient autologous cell culture and can pass the blood-brain barrier.
What are the advantages of exosomes as drugs?
Exosome therapy, as a new treatment method, brings some new opportunities for the current treatment of some refractory diseases or the development of drugs with difficult drug targets.
Stem cell-derived exosomes can also play a role in promoting cell regeneration or repair. In this way, it can play a role instead of stem cells, thereby avoiding the risk of immune infection and cancer caused by stem cell therapy.
The expression of tissue antigens on the surface of exosome membranes provides a biological basis for the development of organ, tissue or cell division drugs.
In addition, exosomes have low immunogenicity, do not cause adverse reactions in the immune system, can be repeated, and can pass non-invasively through many tissue barriers (such as blood-brain barrier, etc.).
Learn More about Our Ability of Exosome Drug delivery
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Isotopes refer to different atoms of the same element, whose atoms have the same number of protons but different numbers of neutrons. The discovery of isotopes makes people have a deeper understanding of atomic structure. This not only gives a new meaning to the concept of elements, but also significantly revolves the benchmark of relative atomic mass, which confirms that the proton number, also called the nuclear charge number, is the key to the chemical properties of elements, not the atomic mass number.
Properties of isotopes
The chemical properties of elements mainly depend on the outer electronic configuration of elements, while isotopes are one of two or more atoms of the same chemical element with the same atomic number, occupying the same position on the periodic table of elements, so their chemical properties are almost the same, but the atomic mass or mass number is different, thus their mass spectrum properties, radioactive transformation and physical properties are different.
Isotopes that exist naturally in nature are called natural isotopes, and synthetic isotopes are called man-made isotopes. If the isotope is radioactive, it will be called radioactive isotope. Every element has radioactive isotopes. Some radioisotopes exist in nature, while others are artificially produced by bombarding stable nuclei with nuclear particles, such as protons, alpha particles or neutrons.
Isotope labeled method
Isotopes can be used to track the movement and change rule of substances. Isotopes are called tracer elements when they are used to track the movement and change of substances. Isotopic labeling refers to the labeling that atoms in compounds are replaced by tracer atoms of its radioactive isotopes or stable isotopes. The chemical properties of compounds labeled with tracer elements are unchanged. Scientists can find out the detailed process of chemical reaction by tracing compounds labeled by trace elements. This scientific research method is called isotope labeled method. Isotope labeled method is also called isotopic tracer technique.
Application Fields
The application of isotope technology has attracted increasingly attention, and many isotopes have important uses, for example, 12C is an atom used as a standard for determining atomic weight; two kinds of H atoms are materials for making hydrogen bombs; 235U is the material for making atomic bombs and the raw material for nuclear reactors; the course of esterification reaction was confirmed by O-labeled compound, and so on. Isotope labeled method is widely used in national defense scientific research, industrial and agricultural production and medical technology. Research on the application potential of isotopes in different aspects is of great significance to human life and development.
Medical Industry
Medical isotopes refer to radioactive isotopes that can be used for disease diagnosis and treatment. They usually play an irreplaceable role in diagnosis and treatment of malignant tumor, cardiovascular and cerebrovascular diseases, etc. The commonly used medical isotopes for stacking in the world include 99Mo/99mTc, 125/131I, 89Sr, 32P, 177Lu, 90Y, 14C, etc. Isotopes have played an important role in immunology, molecular biology, genetic engineering research and development of basic nuclear medicine.
Bio-medical Industry
The most important application of isotope tracer technique in biological science is to study the metabolic transformation of substances, in other words, to study the biochemical processes in life activities. The tracer technology not only establishes the relationship between precursors and products in metabolic transformation, explores the precursors and products of substances, and it’s also often used to discuss how metabolic transformation is completed. In addition, isotopic tracer technique can measure the renewal rate of metabolites in tissues. It also confirms that many macromolecules in the body are synthesized from small molecules.
Nuclear energy Industry
Nuclear energy involves many fields such as nuclear medicine, nuclear power, radiation technology and isotopes. An essential aspect of peaceful use of nuclear energy is also an important part of the nuclear industry serving the national economy and people's lives. Radioisotope is an important aspect of nuclear energy utilization. The energy released by radioactive isotopes during nuclear decay can be used to manufacture isotope batteries. The radioactive isotope is also used for fission reaction in nuclear power plants or used for manufacturing nuclear weapons, and so on. With the development of isotope production, the application of nuclear technology in many departments has been further promoted, and obvious economic and social benefits have been achieved.
Agriculture Industry
In agriculture, isotopic tracer technique is used to study the rational use of pesticides and fertilizers and soil improvement, which provides new measures for increasing agricultural production. Isotope technology has gradually been regarded as a powerful tool for tracing soil sources and studying soil cycle. Other research work, such as food preservation by radiation, has also made great progress. By adopting radiation method or combining radiation with other methods has cultivated excellent varieties of crops, which have greatly increased the production of crops such as grain, cotton and soybean. It is of great significance to the survival and development of mankind.
Environmental aspects
Environmental isotopes refer to natural isotopes widely existing in nature, such as H, C, N, O, S, etc., which are basic elements in hydrological, geological and biological systems. Isotopic hydrogeology is the product of the development of modern nuclear technology. The main basis for obtaining groundwater system information by isotope technology is that stable isotopes play a role in marking water and radioactive isotopes play a role in timing water. A large number of hydrogeology studies have used isotopes in water molecules to judge groundwater source, water quality, recharge mechanism, water-rock reaction, groundwater age and its renewal ability. With the development of analysis and testing technology, people pay more and more attention to the application of isotope technology of low concentration and trace elements in groundwater. By using stable isotope technology, ecologists can detect many ecological processes that change with time and space without disturbing the natural state of the ecosystem and the nature of the elements.
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As an amphiphilic polymer, PEG can be soluble in water and most organic solvents, and has the characteristics of good biocompatibility, non-toxicity, and low immunogenicity. It can be excreted through the kidneys, so there will be no accumulation phenomenon in the body. For a long time, PEG is a commonly used as pharmaceutical excipient, which has been widely applied in various medicaments such as soft ointment, suppository, drop pill, hard capsule, eye drop, injection and tablet.
Role of PEGs
Solubilizers
Resistance to mould growth and rancidity makes PEG an ideal excipient for liquid dosage forms. PEGs minimizes the need of harsh solvents needed during encapsulation. For example, Liquid PEGs (PEG 200 to PEG 600) can be used as a water miscible solubilizer in oral liquids and parenterals. High MW PEGs have been widely used for microencapsulation of active drug. PEG can be used as a lubricant in eye drops.
Permeation Enhancer
PEGs itself possess poor ability of skin penetration due to steric hindrances in conjugation with water molecules. However, skin with compromised barrier and burns (>20%) increases PEG penetration irrespective of molecular weight (Mw). Hence, non-permeable PEG is the most preferred base for transdermal patches. They can be easily removed from skin surface by washing. Because of these properties, solid PEGs are useful in lotions, ointment, and suppository bases.
Release Modifiers
Physically entrapped drugs in PEG matrix is released either through diffusion or erosion-controlled mechanism or combination of both. Water permeates through the shell to the inner core and dissolves the drug followed by diffusion. However, for self-assembled copolymers below critical aggregation concentration (CAC) value, micelles are dissociated into drug-copolymer unimers that would be lysed by autocatalysis or released by diffusion later. Water permeated in this system does not solubilize the drug due to its strong bonding by chemical linkages. PEG 3000 to PEG 5000 follow erosion-controlled drug release mechanism which results in sustained release.
Binders & Plasticizers
In solid dosage formulations, PEGs with high Mw play a role of enhanced tablet binders (Mw >1000) and plasticizers. Low Mw PEGs are liquid at room temperature and can be directly used as plasticizers. High Mw PEGs can also be used as plasticizers, but only when they are dissolved in a solvent or melted to be in a solubilized state. Moreover, PEG can also be used for taste masking of bitter drugs like odansentron HCl (PEG 6000) by forming solid dispersed granules.
Plasma Expanders & Blood Substitutes
The type of high viscosity plasma expanders like PEG-albumin has shear-thinning properties, which can help to increase micro-vessel wall shear stress in microcirculation and thus lead to lower expenditure of energy in systemic circulation. PEGylated hemoglobin (Hb) has been studied to overcome the nephrotoxicity of a cellular Hb, and as an oxygen-carrying plasma expander. Furthermore, Hb modified with PEG 750, 1900, 4000, or 5000 has also been studied as oxygen carrier and as a substitute for red cell (artificial blood).
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Staudinger ligation is to capture the intermediate of azaylide with electrophilic groupsgenerally located on triaryl phosphines, and act in aqueous medium to obtain the intramolecular amido phosphine oxide after rearrangement.
Introduction
Staudinger ligation is a metal-free catalytic click reaction between organic azide and phosphine and it belongs to a bio-orthogonal reaction. It has the following three elements: the reaction must occur in aqueous solution, the catalyst or reactant involved in the reaction is non-toxic, the two functional groups do not exist in the biological system and do not cross-react with any functional group in the biological system.
Ligation mechanism
In staudinger reduction reaction, the reaction of azide and triphenylphosphine (TPP) firstly releases nitrogen to generate intermediate phosphine imine, and then spontaneously hydrolyzes in aqueous solution to generate primary amine and stable triphenylphosphine oxide (TPPO). The reaction mechanism of staudinger ligation is different from the classical reduction reaction. After improvement, TPP is constructed by using the ester located in the ortho position of the phosphine atom in the reactant through intramolecular cyclization reaction as an electrophilic trapping agent, which can capture the nucleophilic azalactium salt intermediate as an amide under the condition of aqueous solution, thus realizing the covalent "binding" of the two molecules. Traceless staudinger liagtion is a further improvement on the basis of staudinger liagtion. Its "traceless" is reflected in the formation of amide bonds in the hydrolysis step and the removal of TPPO from the final product[1].
Influence factor
The influence of reaction influencing factors on the yield mainly lies in whether the reaction is promoted to proceed in the direction of staudinger ligation.
Polarity of solvent in reaction system
Position and structure of functional groups in reactants
PH of functional groups in reactants
Water solubility of functional groups in reactants
Stability of functional groups in reactants
Application
As a representative of metal-free catalytic click reactions, staudinger ligation plays an important role in various complex biological systems. At present, Staudinger ligation has been widely used in biomarkers, target material delivery and so on.
Application in biomarkers
Phosphine and azide in staudinger ligation have bio-orthogonal characteristics. The chemical inertia of azide determines its molecular size and high stability under physiological conditions, making it very suitable for biological coupling and widely used for biomolecule labeling.
Staudinger ligation can be used in marking nucleic acid molecule such as RNA and DNA. For example, RNA is labeled with a fluorescent substance modified with an azide group, and the imaging of RNA in mammalian and bacterial cells is realized by templated stoodinger ligation. Staudinger ligation mediated glycan labeling provides a new possibility for realizing the visualization of glycans participating in various biological processes in the native environment and detecting intracellular interactions. Staudinger ligation doesn’t affect phage viability, and enrichment could be easily achieved after ligation. Therefore, staudinger ligation can selectively modify protein without changing its function, and can be applied to produce highly uniform PEGylated proteins and surface-immobilized proteins.
Application in biosensors
Because the ester leaving groups generated in the staudinger ligation can be designed for specific biological applications, staudinger ligation is often used in fluorescent biosensors, providing a fast and convenient method to detect nucleic acids and small molecules.
For example, a reduction triggered fluorescent probe is used to detect oligonucleotides. The new fluorescent compound in the probe is a kind of rhodamine derivative labeled on the DNA strand complementary to the target strand. The azide group in the probe can be connected with the TPP labeled on the other DNA strand by staudinger ligation. After the azide group is reduced, a fluorescent signal appears. The probe has been successfully applied to detect oligonucleotides at single nucleotide level in solution and endogenous RNA of bacterial cells.
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