Polymer functionalization aims at imparting new properties (e.g. chemical, biophysical, physicochemical or optoelectronic) to materials. Functional polymers have been developed for a wide range of diverse applications. These include organic catalysis (supported catalysts), medicine (red-blood-cell substitutes), optoelectronics (conducting polymers, magnetic polymers and polymers for nonlinear optics), biomaterials, paints and varnishes, building materials, photographic materials as well as lube and fuel additives. While it is not possible to enumerate all of the applications of functional polymers, some representative examples of functional polymers are listed below.

Polymer supported catalysts have advantages because of the ease of catalyst recovery and the opportunity for simultaneously using otherwise incompatible catalytic systems. Indeed, the immobilization of several catalysts onto a polymer matrix is a unique way of avoiding antagonistic reactions between them, and of allowing reagents to participate in a ‘cascade’ of reactive processes. For example, polymer-supported catalysts have been used as the Lewis acid catalysts in the carbocationic polymerization of isobutylene. After the reaction, polyisobutylene is obtained by simply filtering the supported catalyst. The reaction cycle can be repeated many times.

Metal containing polymers are useful for a wide range of applications including analysis and catalysis, optical and electronic devices, colorants and coatings, structural composites, ceramics, controlled-released medicaments, and biocides.

Photosensitive polymers can be applied in areas such as printing, electronics, paints, biomaterials, information recording, and UV curing inks. One of the major applications of photosensitive polymers is in the development of resist materials with submicron resolution for semiconductor fabrication. Resist science and technology is an expanding field, and there is an increasing demand for more sensitive photopolymers and exposure equipment. Thus, the new photosensitive polymers will continue to make significant contributions to electronic and photonics through improvements of material and related technologies, especially for deep-UV, electron beam, and X-ray lithography and chemical amplification resist systems.

Liquid crystalline polymers offer a range of properties that include ferroelectric behavior that has potential for fast switching devices, piezo- and pyroelectric properties. The ability of liquid crystalline polymers to improve hardness and impact strength can impact the coating industry. The self-assembling properties of liquid crystalline polymers coupled with the development of new block copolymers containing liquid crystalline units, which can also undergo microphase separation, could also yield new materials with increased strength.

Conducting polymers are polymers having a conjugated backbone structure that is capable of being doped to yield high electronic mobility and electrical conductivity. The delocalised electronic structures of 7c-conjugated polymers, which are responsible for their unusual electronic properties, tend to yield relatively stiff chains with little flexibility and with relatively strong inter-chain attractive interactions, which make them insoluble and non-processable. Such monomers have been modified to obtain polymers that are soluble in water and organic solvents. Potential applications include solid-state rechargeable batteries, “smart” windows, photo- or electrochromic materials, antistatic coating, sensors, photocells, and electromagnatic screening applications.

Some of these polymers have the ability to be electroluminescent for use in plastic light emitting diodes (LED). Optical components (including transmitter, receiver, modulator, couplers, multiplexing system, and data links) could be manufactured from specifically tailored functional polymers in the near future.

Functional polymers may be used for different types of chemical sensors, including acoustic wave sensors (bulk acoustic wave, surface acoustic wave, and flexural plate wave sensors), electronic conductance sensors (semiconducting and capacitance sensors), and calorimetric sensors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has generated a fast response from the global scientific community, governmental organizations, the life sciences industry, and healthcare providers. With unprecedented speed, a number of laboratory tests have been developed with the aim to facilitate easy and efficient detection of virus infection, and tests are emerging for the measurements of antibodies for identifying past SARS-CoV-2 infections.

As the pandemic evolves, it is becoming clear that there is a gap between the ambition and the usefulness of these tests. Evidence continues to accumulate on the limitations of the currently available diagnostic and prognostic approaches.

Coronavirus disease 2019 (COVID-19) assays can be distinguished in (1) virus detection assays (nucleic acid and imaging based), (2) immunity assays (serological or immune cell based), and (3) prognostic assays reflecting severity of disease, complications and degree of recovery (miscellaneous biomarker testing).

In particular, serological tests are becoming more relevant as they are able to detect past COVID-19 infections. However, many open questions remain around each test’s specificity and sensitivity, which represents its validity and usefulness in a clinical setting. The value of these tests, as with many other biomarker tests in healthcare and patient management, is one of today’s major challenges.

In addition to SARS-CoV-2 detection and testing of immune response, there is an urgent need to predict which patients will develop specific disease characteristics. Indeed, some individuals develop mild symptoms and others very severe ones for unknown reasons, and patients can differ dramatically in the degree and speed of their response following hospitalization. Recent studies showed how COVID-19 patients with comorbidities, such as hypertension or diabetes mellitus, are more likely to develop a more severe course and progression of the disease. Differences in the immune response or prior coronaviruses infections could also affect the COVID-19 clinical course.

This heterogeneity of manifestations of SARS-CoV-2 infection constitutes one of the greatest challenges in managing the clinical consequences of the pandemic. Biomarker profiles are of vital importance to clinicians when evaluating treatment options, for defining the clinical course, and for close monitoring and support of patients in their disease management and remission trajectory.

Tools should enable population screening and the identification of high-risk patients. Given the large interindividual heterogeneity, this can be achieved using biomarker signatures, composed of multiple analytes. Given their relevance in this context, robust and well-validated biomarkers are crucial to enable effective decision-making.

SARS-COV-2 TESTING: CURRENT SITUATION

SARS-CoV-2 and COVID-19 testing kits are designed to be used in routine laboratories and also at the point-of-care setting, with the ambition of shortening the diagnostic time window and thereby facilitating rapid identification of COVID-19 positive patients and contacts. In order to be effective, these kits must be based on validated biomarkers and biomarker assay formats that yield high sensitivity and specificity results, for instance, to distinguish an infected person from a noninfected one.

SARS-CoV-2 diagnostic tests are based on the detection of the viral genome (eg, reverse transcription polymerase chain reaction (RT-PCR)-based methods, isothermal amplification assays and CRISPR), viral proteins (eg, antigen-based test), or antibodies against the virus (eg, serological test).

Methods based on the viral genome detection, with their large range of applications, high sensitivity, and high sequence specificity, have become a routine and reliable technique for detecting.

To complement the viral genome tests, viral antigen tests have been developed. These tests allow the virus detection early in infection but display limitations on sensitivity and potential cross-reaction with other coronaviruses.

Despite the fact that COVID-19 is a severe pandemic, many governments are leaning toward “mitigation” and “containment” as strategies. The overarching goal is for all countries to control the pandemic by slowing down the transmission and reducing mortality associated with COVID-19. Indeed, in the absence of a vaccine, reaching group immunity is no straightforward path with major ethical considerations as the societal consequences of achieving it are devastating. Mobility and travel restrictions, social distancing, and the use of personal protective equipment have been introduced in order to reduce human-to-human transmission. The use of face masks in particular is enforced widely within the general population, together with hand hygiene.

Stopping the spread of COVID-19 requires finding and testing all suspected cases so that confirmed cases are promptly and effectively isolated and receive appropriate care. It is important that the close contacts of all confirmed cases are rapidly identified, quarantined, and medically monitored for the virus incubation period of up to 14 days.

Next to the need for well-validated and reliable diagnostic tests, this scenario demands high quality and reliable serological tests, measuring the immune responses induced by past and new viral infection, in combination with tests addressing T-cell activity. These assays are important for understanding the prevalence of COVID-19 and whether the development of a humoral immune response to SARS-CoV-2 protects against the disease.

As the World Health Organization (WHO) clearly underlined, “Laboratory tests that detect antibodies to SARS-CoV-2 in people, including rapid immunodiagnostic tests, need further validation to determine their accuracy and reliability” (https://www.who.int/news-room/commentaries/detail/immunity-passports-in-the-context-of-covid-19). Addressing these issues is crucial, as serological assays are critical for the patient care pathway and for the management and surveillance of the virus.

Limitations to the use and development of the tests described above include poor test sensitivity due to sample collection, poorly described reference material, low specificity, and lack of technical validation, and therefore a threat of false disease diagnosis.

Uncertainty in test sensitivity that lead to false-negative cases of COVID-19 likely constitutes a serious threat to the control of the pandemic. Indeed, false negative results are more weighty, because unrecognized infected persons may not be isolated and can infect others [4]. Because of this, some governments require RT-PCR test and quarantine for people who are considered close contacts of positive cases, with additional testing and isolation in case of negative results. Moreover, in presence of a strong epidemiological link to COVID-19 infection, paired serological tests (in the acute and convalescent phase) could support diagnosis.

Testing limitations are likely a result of combining several unknowns such as the lack of understanding of the biology of the disease, in particular its natural history and associated immune response, a relatively low number of samples, and the use of novel laboratory test kits whose quality and accuracy has not been rigorously tested. Furthermore, the lack of rigorous study design and methodology to robustly validate the tests before deployment affects the tests’ reliability and ultimately the correctness of the clinical assessment.

COVID-19 research is still in its early stages, and we need further research worldwide to better face this pandemic. We still need to learn about the biology of the disease and the variable response that patients display in their disease manifestation and recovery. We expect that the process of biomarker discovery and validation will largely guide an accelerated translational strategy to address this global health crisis. A standardized pathway approach toward the biomarker validation process is thus becoming increasingly important. Quality and reproducibility are essential for translating basic findings into concrete clinic interventions and only following this approach is an effective response to the pandemic guaranteed. Significant efforts and resources have been invested in the development of biomarkers for COVID-19 and AMRI urges that research must be of good quality, providing robust, ethical evidence that stands up to scrutiny and can be used to inform policy making. For COVID-19 management, structural use of the relevant research infrastructures is strongly advised, as they play an important role in centralized management of biomarkers R&D pipelines, biobanking, and clinical trials. The collective efforts of AMRI and collaborative actions of the scientific community will create high-quality knowledge that is openly available and will bring a better understanding of SARS-CoV-2, with benefits for all.

Bioceramic materials have a long history of being used for repairing human hard tissues. From bioinert materials (such as alumina and zirconia, etc.) to bioceramics (such as phosphate and silicate bioceramics, silicon-based bioglass, etc.) with both biological activity and degradability, their physiological function requirements are no longer simple tissue filling substitutes, but tissue engineering materials that can induce tissue regeneration, regulate cell growth and functional differentiation. There is increasing evidence that specific bioactive ceramic materials have the effect of promoting the revitality of soft/hard tissue-specific cells and are widely used in tissue defect repair of bones, teeth, and skin. However, there are many special tissue injuries in clinical practice, such as tissue defects after surgical resection of bone tumors or skin cancer tissues, which require the removal of residual tumor cells before repairing the tissue defects to avoid tumor recurrence. In order to realize the dual functions of cancer therapy and tissue regeneration, previous studies have prepared photothermally functionalized bioactive ceramic materials by compounding bioactive ceramics with photothermal reagents with cancer therapy functions. Despite an effective strategy, the long-term safety of photothermal nanoreagents in vivo has yet to be investigated. Therefore, how to realize the integration of tissue regeneration of bioactive ceramic materials themselves and the therapeutic function of diseases such as tumors without introducing foreign additives is particularly important.Recently, the research team led by Wu Chengtie and Changjiang, researchers at the Shanghai Institute of Silicate, Chinese Academy of Sciences, has made progress in the study of multifunctional black bioactive ceramic materials. The research team developed a new generation of “black bioactive ceramics” by thermally reducing traditional white bioactive ceramic materials (silicates and phosphates, etc.), expanding the application field of traditional bioactive ceramic materials from tissue regeneration to the treatment of diseases such as tumors. The relevant research results were published in Advanced Materials under the title Black Bioceramics: Combining Regeneration with Therapy and applied for a patent.

The team used magnesium thermal reduction to thermally reduce traditional white bioactive ceramic powders to prepare a series of black bioactive ceramic materials, including bioactive ceramics with two systems: silicate (i.e., CaSiO3, MgSiO3) and phosphate (i.e., Ca3 (PO4) 2, Ca5 (PO4) 3 (OH)). Compared with traditional white bioceramics, black bioceramics have a large number of oxygen vacancies and structural defects in the crystal interior, and their degradation properties are significantly improved, which has a better promoting effect on cell biological activities such as adhesion, spreading, proliferation, migration and differentiation of osteoblasts and skin cells.

In animal experiments of chronic skin trauma and massive bone defect repair, black bioceramics are significantly superior to white ceramics for skin and bone tissue repair, showing a significant promotion of soft/hard tissue multifunctional revitality. In addition, under low-power near-infrared light irradiation, black bioactive ceramic materials show significant photothermal heating effect, which can lead to tumor cell death around the materials, successfully inhibit the growth of skin cancer and bone tumors in vivo experiments, and have excellent photothermal anti-tumor effect. In summary, black bioactive ceramic materials have multifunctional characteristics such as promoting the revitalization of a variety of tissues and cancer treatment, and this study expands the application range of bioactive ceramics from tissue regeneration to cancer treatment, strongly promoting the subject development and clinical application of bioceramics.

The R&D of a COVID-19 vaccine that has received much attention was once again pressed the pause button.

Johnson & Johnson announced on the 12th that the company decided to suspend clinical trials of the COVID-19 vaccine candidate developed by its subsidiary Janssen Pharmaceuticals due to an “unexplainable disease” of a subject.

Johnson & Johnson issued a statement on the same day that the company will suspend all clinical trials of the vaccine, including phase 3 clinical trials initiated at the end of September. Currently, an independent committee and relevant experts are investigating and evaluating the subject’s illness. According to the statement, adverse events such as diseases and accidents are possible situations in any clinical research, especially large-scale ones. All clinical studies conducted by Janssen Pharmaceuticals have preset guidelines to ensure that the study can be suspended once an unexpected serious adverse event related to the vaccine or drug under development is discovered, and decisions of whether to restart the research will be published after the investigation is clear. Since many clinical trials are randomized, double-blind controlled trials, it is often not immediately clear whether the subjects received the experimental treatment or a placebo.

The suspended candidateis a recombinant adenovirus vector vaccine, of which the phase 3 clinical trial launched on September 23, and planned to recruit approximately 60,000 adult volunteers in approximately 215 locations in the United States and other parts of the world. It is the fourth COVID-19 vaccine candidate to undergo phase 3 clinical trials in the United States.

On September 8th, a large-scale phase III study of another COVID-19 vaccine developed jointly by AstraZeneca and Oxford University was put on hold because of a suspected adverse reaction from a patient in the UK, who had transverse myelitis. R& D of the vaccine was suspended for about a week in the UK and has resumed. In the United States, however, the project is still on hold.

Preclinical & Clinical Trials

Long and complicated as it is, vaccine R&D is full of uncertainty at each step. The development cycle is often 5 to 10 years. Under special circumstances, in order to block the outbreak of acute infectious diseases as soon as possible, the approval cycle can be greatly shortened by using basically the same technology, the same cultured cells, the same adjuvants, and the same raw materials as the existing vaccines.

The development of vaccines is roughly divided into two steps: preclinical research and clinical research, among which pre-clinical research is a prerequisite.

Antigen Discovery

Look for protective antigens that can produce protective antibodies or induce cellular immunity. In general, inactivated or attenuated viruses are often used as candidate antigens.

Safety Evaluation

The safety studies mainlyverify the long-term toxicity, acute toxicity, local irritation, and allergies of the vaccinein vivo through animal models.

Potency Assessment

If the vaccine candidate can protect the existing model animals from the disease after the viral attack, and there is no antibody-dependent disease enhancement (ADE) effect, it can be a truly effective vaccine candidate.

Regarding the 3 clinical trials of a vaccine candidate, Phase I tested its safety, and Phase II continues to ensure safety, and more importantly, its effectiveness, which mainly tested whether antibodies can be produced, and the quantity, time, and duration of the antibodies. In the third phase, a large number of people are vaccinated to observe whether there is any substantial protective effect in the epidemic area.

Johnson & Johnson did not disclose the recovery time and referring to AstraZeneca’s case, recovery may not be as easy as imagined.On September 12, the Oxford University team revealed that the vaccine, jointly developed with AstraZeneca, resumed clinical trials in the UK, only 4 days after the suspension, whileon September 16, according to Reuters, it resumed trials in Brazil and India, which is only 8 days since the suspension was announced on September 8. However, in the United States, trials of AstraZeneca’s vaccine have not been approved to resume by now.

On November17, 2020, Alfa Chemistry Materials, an expert in specialized materials, announces to release a range of crosslinking agents for the global market, which could be used for the betterment of polymer materials.

As crosslinking agents can transform linear or lightly branched macromolecules into a three-dimensional network structure and improve their performances in regard with strength, wear resistance, heat resistance, and solvent resistance, they are widely added to resins.

“Crosslinking is a type of polymerization reaction that branches out from the main molecular chain to form a network of chemical links, and in this process, cross-linking agents are added to resins,” says a senior scientist from Alfa Chemistry Materials. “Cross-linking agent works by creating chemical bonds between the linear molecules, so as to improve the strength and elasticity of the rubber.Crosslinking has been employed in the synthesis of ion-exchange resins and stimuli-responsive hydrogels made from polymer molecules containing polar groups. ”

With chemical cross-linking techniques, new polymer derivatives that completely have different physical and chemical properties can be produced. Therefore, the application of crosslinking agents is far more wide-ranged than what the scientist said above, which include:

l Crosslinking and modification of various thermoplastics

l Crosslinking of acrylic and styrene ion exchange resins

l Modification of polyacrylate, polyalkyl acrylate

l Modification of epoxy resin and DAP (polyallyl phthalate) resin

l Crosslinking and modification of unsaturated polyester and thermoplastic polyester

l Used as an intermediate for light-curing coatings, photoresists, flame retardants and flame-retardant cross-linking agents

“After cross-linking, properties like thermal degradation, glass transition, particle size, pore size, pore volume, surface area, and swelling are totally changed. For example, cross-linking agents can transform polyethylene (PE) from being a basic commodity thermoplastic into a useful engineering material. Meanwhile, controlled cross-linking also provides enhanced properties like heat resistance and durability in PE applications in medical, foam, pipe, wire & cable, and other fields.

The crosslinking agentsavailable at Alfa Chemistry Materials include: p-Divinylbenzene, Triethylene glycol dimethacrylate, Divinylbenzene, Tetra(ethylene glycol) diacrylate, Tetraethylene glycol dimethyl ether and many more.For more details, please visit https://materials.alfachemic.com/products/crosslinkers-412.htmlor email us directly.

About Alfa Chemistry Materials

With the aim to continuing serving clients from universities, research institutes as well as other organizations, Alfa Chemistry Materials strives to broaden and enhance its product offerings by providing micro-nano electric materials, nanomaterials, organic and printed electronics, photonic and optical materials, polymers and many other material chemicals. The in-stock products listed on the website can be shipped out within 3-5 business days upon receipt of customers’ purchase order.

Superoxide dismutase (SOD) is a biological enzyme that protects the body from oxidative damage and has significant protective effects on the body. It is widely distributed in animals, plants and microorganisms. SOD has the ability to scavenge superoxide free O2-in the body, and can better resist the toxicity of oxygen free radicals and other oxide free radicals on the plasma membrane of the cell and maintain the normal physiological metabolism of the cell. Therefore, SOD is widely used in the pharmaceutical, food and cosmetic industries.

1) Pharmaceutical industry: In clinical applications, SOD is mainly focused on inflammation, autoimmune diseases, especially rheumatoid arthritis, emphysema, lupus erythematosus, oxygen poisoning and senile cataract, aging and various skin diseases. However, the medical field has high requirements for the safety of SOD. Therefore, Cu and Zn-SOD extracted from plants are gradually adopted due to their good safety and low production cost. Plants contain SOD resources, only corn has a large yield.

2) Food industry: SOD can be used as a health food’s efficacy factor, food nutrition fortifier, compound food raw materials, antioxidants, anti-oxidant fresheners, etc. At present, the International Schistosomiasis Organization has banned the extraction of SOD from blood as raw materials for medical and health products.

3) Cosmetics industry: SOD is the only active industrial enzyme recognized by the international scientific community that can eliminate harmful free radicals produced by the human body during metabolism. It is one of the substances approved by the International Ministry of Health with anti-aging, immune regulation, anti-radiation and beauty functions .

According to the “2017-2020 SOD Industry Market In-depth Investigation and Investment Strategy Research Report” released by the Industry Research Center, in recent years, with the development of the pharmaceutical, food, cosmetics industry and technological progress, The scale of the dismutase SOD market continues to expand.

Market development prospects

Superoxide dismutase is quite delicate and has three characteristics: “difficult to extract, difficult to preserve, and difficult to absorb”. These three major problems have also plagued the world for nearly 40 years. Up to now, SOD is still a high-level, sophisticated and sophisticated biological science topic. The SOD extraction process is extremely complicated and the output is extremely limited, so related products are extremely rare and expensive.

In the upper classes of society of Europe and the United States, SOD health products have become synonymous with top luxury products with excellent efficacy, scarce production and expensive prices, and are favored by high-end user groups. In the United States, SOD, as an important raw material, has great market potential in the fields of medicine, food, and cosmetics, and has a good future development prospect.

Investment potential

Superoxide dismutase is internationally recognized as the “scavenger”, “anti-aging king” and “beauty beauty” of human waste. It is the most powerful substance against active oxygen free radicals. The research and development represents the forefront of the development of high-tech technology in biomedicine, occupying an important international position in scientific and technological achievements and academic fields.

The superoxide dismutase industry in some developing countries is still weak. Take China as an example. In recent years, China has continuously promoted the research of superoxide dismutase and promoted the industrialization of products. However, China’s current industrialization capacity is still limited, the scale of enterprises is generally small, and the domestic market is occupied by foreign companies. The major Chinese companies include Siping Huake Biotechnology Co., Ltd., Zhejiang Maikang Biological Engineering Co., Ltd., and Liaoning Weilin Biotechnology Development Co., Ltd.

Abstract: With extensive experience in the field of nanoparticles, magnetic particles and magnetic beads, Creative Diagnostics now offers a wide range of Anti-Coronavirus Antibodies Conjugated Magnetic Particles Immunoprecipitation Kits to worldwide scientists.

Immunoprecipitation technique is mainly used to isolate an antigen by binding to a specific antibody attached to a sedimentable matrix. There are several types of immunoprecipitation, including individual protein immunoprecipitation (IP), RNP immunoprecipitation (RIP), protein complex immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), etc.

Magnetic beads are particularly applicable for immunoprecipitation because they are all accessible to an antigen if antibodies are bound to their surface, in addition, these antibodies have little chance to be lost in the steps of washing. What’s more, magnetic beads can provide high reproducibility and purity since they are uniform in size and the interactions occur on their outer smooth surface.

Creative Diagnostics now offers a series of magnetic immunoprecipitation kits for coupling of target antibody, covering various kinds of anti-coronavirus antibodies conjugated magnetic particles immunoprecipitation Kit. The featured products include:

·MagIso™ Anti-SARS-CoV-2 (2019-nCoV) Spike Magnetic Particles Immunoprecipitation (IP) Kit

·MagIso™ Anti-SARS-CoV-2 (2019-nCoV) Spike S2 Magnetic Particles Immunoprecipitation (IP) Kit

·MagIso™ Anti-SARS-CoV-2 (2019-nCoV) Spike RBD Magnetic Particles Immunoprecipitation (IP) Kit

·MagIso™ Anti-SARS-CoV/SARS-CoV-2 Spike S1 Magnetic Particles Immunoprecipitation (IP) Kit

·MagIso™ Anti-MERS-CoV Spike Protein S1 Magnetic Particles Immunoprecipitation (IP) Kit

With these products, the immunoprecipitation experiment can be completed within 30 min and they can also process multiple samples easily and rapidly. In addition, small benchtop instrumentation is available for the automation of the whole immunoprecipitation protocols using magnetic beads.

“Immunoprecipitation is ideal for analyzing protein fractions which are separated by other biochemical techniques, and both monoclonal and polyclonal antibodies from various animal species can be used in immunoprecipitation protocols.” introduced by a senior scientist at Creative Diagnostics.

“The standard and quality products will be delivered as soon as possible when the order is placed. If there are any special needs, our expert team is always ready to provide a customized solution to better facilitate the projects of our clients.” said the project manager.

Other kinds of beads based kits and devices are also available at Creative Diagnostics, including cell isolation kits, organelles isolation kits, DNA extraction and purification kits, and accessories and devices for the handling of magnetic beads products and kits. Detailed information about these products can be reached on https://www.cd-bioparticles.com/.

About Creative Diagnostics

Creative Diagnostics is a leading manufacturer and supplier of various nanoparticles, microparticles and their coatings for R&D and commercialization in a wide variety of application areas including in-vitro diagnostics, biochemistry, cellular analysis, cell separation, immunoassay.Creative Diagnostics is also dedicated to providing the most comprehensive list of products and fit-for-purpose custom design services to academia as well as industrial researchers and assay developers all around the world.

3. 3. Ramucirumab for tumor treatment

Ramucirumab is a fully humanized immunoglobulin G (IgG) 1 monoclonal antibody, a polypeptide molecule composed of two heavy chains and two light chains. Ramucirumab can specifically bind to the extracellular domain of VEGFR-2 and block the interaction between VEGFR-2 and its ligands. Among them, VEGFR-2 is the main receptor that mediates and regulates the downstream ligand VEGFR-A. The binding affinity of ramucirumab to VEGFR-2 is about 8 times that of the natural ligand VEGFR-A. After ramucirumab binds to VEGFR-2, it induces changes in its conformation and steric hindrance to interfere with its binding to ligands and inhibit angiogenesis, thereby blocking the blood supply of tumor cells and leading to tumor cell apoptosis.

Tumor blood supply depends on the blood vessels in the surrounding tissues, which can continue to spread and grow. Clinical studies have shown that blood vessel formation plays an important role in the production of tumors with a diameter of 100~200um. The vasculature of tumor tissues will appear structural disorders and blood vessels due to abnormal angiogenesis. Increased permeability and poor blood supply. In this case, malignant tumors will reduce the use of cytotoxic chemotherapeutic drugs and increase the risk of metastasis. The angiogenesis process is more complicated and requires the participation of pro-vascular production media, such as the vasculature, VEGF, circulating endothelial cells, etc. As an important signal transduction pathway, VEGF can combine with VEGFR-2 and VEGFR-1 in tissue epithelial cells to activate intracellular signal transduction pathways, thereby promoting the formation of new blood vessels and the proliferation of vascular endothelial cells. Malignant tumor progression, stage, shortened tumor-free survival time, ascites formation, overall prognosis, and VEGF expression are closely related. Immunohistochemical examinations show that VEGF is expressed in tumors and metastatic tissues, and it can also be expressed in serum and malignant ascites. detected. VEGFR and VEGF were detected as independent prognostic factors in tumor patients. VEGF is expressed at moderate intensity in borderline tumors, but rarely expressed in normal tissues, and its expression is tumor-specific. In addition, because there are gaps in the basement membrane of VEGF-mediated neovascularization, tumor cells are more likely to spread. Therefore, VEGF plays an important role in tumor growth, tumor metastasis, and ascites formation, and the role of targeted therapy for angiogenesis in tumor treatment has become increasingly prominent.

The pharmacokinetic characteristics of ramucirumab are in line with the nonlinear pharmacokinetic characteristics. With the increase of its dose and the number of administrations, its clearance rate decreases. The REVEL trial is an international randomized, double-blind, placebo-controlled Phase III clinical study to evaluate the efficacy and safety of docetaxel alone and ramucirumab in combination. The study included 1 253 lung cancer patients who had failed first-line treatment with platinum drugs and randomized them. The results showed that ramucirumab combined with docetaxel can significantly improve the survival benefit of patients with metastatic NSCLC. The median survival time (mOS) was 10.5 and 9.1 months, respectively, and the median progression-free survival (mPFS) are 4.5 and 3.0 months respectively; common adverse reactions are neutropenia, fatigue, leukopenia and hypertension. The REGARD trial is an international randomized, multicenter, placebo-controlled, phase III clinical study that included 355 patients with advanced gastric cancer or gastric-esophageal junction adenocarcinoma who had received first-line platinum drugs or fluorouracil chemotherapy. The patients were randomized and given ramucirumab or placebo. The study showed that the mPFS of the ramucirumab group and the placebo group were 2.1 and 1.3 months, respectively, and the OS was 5.2 and 3.8 months, respectively. The adverse reaction during the study was hypertension, with an incidence rate of 8%. The RAINBOW trial is a randomized, double-blind, phase III clinical study to evaluate the safety and effectiveness of paclitaxel alone and ramucirumab in patients with metastatic or unresectable advanced gastric cancer who have failed treatment. The results showed that the OS of the ramucirumab combined with paclitaxel group was significantly longer than that of the paclitaxel alone group, which was 9.6 months and 7.4 months, respectively; ORR was 28% and 16%, respectively; PFS was 4.4 and 2.9 months, respectively. Therefore, ramucirumab became the first anti-angiogenic drug for the treatment of advanced gastric cancer. The REACH trial is a phase III clinical study designed to evaluate the safety and effectiveness of ramucirumab in HCC patients who have received the first-line chemotherapy drug sorafenib. The results showed that the OS of patients in the ramucirumab group and placebo group was 9.2 and 7.6 months, respectively. A phase III clinical study based on the above research results evaluated the safety and effectiveness of ramucirumab in HCC patients with elevated AFP levels. The results showed that the application of ramucirrhizumab treatment in patients with liver cirrhosis will achieve the greatest survival benefit.

Studies have shown that, compared with other anti-angiogenic drugs, the adverse effects of ramucirumab in the target patient population are acceptable. Common adverse reactions of ramucirumab include fatigue, headache, nausea, high blood pressure, leukopenia, anemia, allergic reactions, sensory neuropathy, dyspnea, pneumothorax, proteinuria, hemoptysis, bleeding, anorexia, gastrointestinal perforation, constipation and diarrhea; rare adverse reactions are arterial embolism) and ascites, the incidence is less than 5%. Among them, the most common adverse reaction is hypertension (Grade 3: 8%), but it can be tolerated, and treatment will not be interrupted due to its occurrence.

Ramucirumab is a fully humanized IgG1 monoclonal antibody that can specifically bind to VEGFR-2 and induce its conformational and steric hindrance changes, interfere with its ligand binding, inhibit the formation of new blood vessels, and prevent Cut off the blood supply of tumor cells, leading to tumor cell apoptosis. The pharmacokinetic characteristics of ramucirumab conform to the characteristics of nonlinear pharmacokinetics, and the elimination mechanism is saturated. Currently, ramucirumab has been used for NSCLC, gastric cancer, gastroesophageal junction adenocarcinoma, mCRCs, HCC, RCC, breast cancer, ovarian epithelial tumors, mCRPC, melanoma, recurrent glioblastoma, Clinical research on bladder epithelial cancer, cholangiocarcinoma and pancreatic cancer.

Reference

[1] Bray F，Ferlay J，Soerjomataram I，et al． Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］． CA Cancer J Clin，2018，68( 6) : 394-424．

[2] Miao L，Guo S，Lin CM，et al． Nanoformulations for combination or casade anticancer therapy［J］． Adv Durg Deliv Rev，2017，115: 3-22．

[3] Bhatt L，Sebastian B，Joshi V． Mangiferin protects rat myocardial tissue against cyclophosphamide induced cardiotoxicity［J］．J Ayurveda Integr Med，2017，8( 2) : 62-67

[4] Spratlin JL，Cohen RB，Eadens M，et al. PhaseⅠpharmacologic and biologic study of ramucirumab（IMC-1121B），a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 [J]. J Clin Oncol，2010，28（5）：780-787

[5] Franklin MC，Navarro EC，Wang Y，et al. The structural basis for the function of two anti-VEGF receptor 2 antibodies[J]. Structure，2011，19（8）：1097-1107.

[6] Kajitani T，Makiyama A，Arita S，et al． Anti-Epidermal growth factor receptor antibody readministration in chemorefractory metastatic colorectal cancer［J］． Anticancer Res，2017，37( 11) : 6459-6468．

Ovarian cancer is a disease with high mortality among gynecological malignancies. The positive rate of Her2 in ovarian cancer is similar to that of breast cancer, about 15%-30%. Use Trastuzumab conjugate (T-DM1) to treat human ovarian cancer cells. T-DM1 can significantly inhibit cell proliferation. Cells were inoculated into nude mice and administered at doses of 10 and 30 mg/kg. The results showed T-DM1 can significantly reduce the weight of tumors and exhibit significant anti-tumor effects. It can be seen that the positive expression of Her2 is closely related to the overall survival of patients with ovarian cancer. The use of T-DM1 against ovarian cancer cells has a significant anti-tumor effect. Her2 is positively expressed in gastric cancer, and its positive rate is about 6% to 30%. In different gastric cancer cell lines, Trastuzumab can inhibit the expression of Her2/neu and inhibit the proliferation of tumor cells. In addition, in SNU-216 cells, Trastuzumab can regulate cell G1 arrest, increase the expression of p27 kip1, phosphorylate Her2, inhibit the expression of downstream STAT3, AKT and ERK signaling molecules, and inhibit cell proliferation; Trastuzumab combined with cisplatin and 5-FU treated cells to produce a synergistic effect. Later, it was found that Trastuzumab combined with a new anti-Her3 antibody (1A5-3D4) can significantly inhibit the phosphorylation of Her3, block the activation of AKT and ERK signaling pathways, inhibit the proliferation of Her2-positive gastric cancer cell line NCI-N87, and enhance Anti-tumor activity of Trastuzumab. It can be seen that targeting Her2 and Her3 can significantly improve the therapeutic effect of Her2-positive gastric cancer. In recent years, studies have found that antibody targeted therapy has become a new direction for lung cancer treatment. Its therapeutic mechanisms mainly include: inhibiting tumor EGFR expression, binding to target molecules on the surface of tumor cells, inhibiting tumor cell proliferation and metastasis, and stimulating immune responses, etc. The positive expression rate of Her2 in lung cancer is 25%-30%, and it is mainly overexpressed in non-small cell lung cancer, and the worse the cell differentiation ability, the higher the positive rate. As an anti-Her2 positive antibody, Trastuzumab has been used in the treatment of small cell lung cancer with poor first-line second-line chemotherapy. A clinical study found that Trastuzumab and irinotecan were administered to patients with Her2 positive small cell lung cancer for 21 days when the first-line second-line chemotherapy drugs were not good. The results showed that this treatment program had a disease progression period of 4.5 months, which had a good Anti-tumor effect, and no serious adverse reactions.

Trastuzumab has a good therapeutic effect on breast cancer, ovarian cancer, lung cancer and gastric cancer with positive expression of Her2, and has no serious adverse reactions. It has been designated as the first-line anti-tumor therapy in many countries. However, its research in ovarian cancer, kidney cancer and prostate cancer is still at a relatively lagging stage. In-depth study of its anti-tumor mechanism will help to screen its anti-tumor biological targets and formulate a suitable anti-tumor spectrum. With the deepening of treatment, tumor cells have developed drug resistance, and the emergence of combination medications has produced positive therapeutic effects. However, it is still unclear how Trastuzumab combination drugs can reverse tumor resistance.

2. 2. Carrelizumab for tumor treatment

Carrelizumab is a humanized IgG4κ type anti-PD-1 monoclonal antibody expressed in the Chinese hamster ovary cell (CHO) cell line using recombinant technology. It binds to PD-1 to block PD -1/PD-L1 pathway, which activates T cells and produces a sustained anti-tumor effect.

T cell is the most important immune component of the body’s immune system. Its functional activity is strictly and precisely regulated by the immune system. The main molecular mechanism lies in the multiple receptor molecules on its membrane that transmit activating or inhibitory signals. While T cells are stimulated and activated by antigens, the immune system also initiates a negative feedback mechanism to avoid excessive activation of T cells and cause continuous and excessive damage to the body. One of the important mechanisms is that a series of inhibitory receptor molecules are expressed on the surface of T cells, including CTLA-4, PD-1, lymphocyte-activating 3 (LAG3), T cell immunoglobulin and T-cell immunoglobulin- and mucin-domain containing 3 (TIM3) is hepatitis A virus cellular receptor 2 (hepatitis A virus cellular receptor 2), containing immunoglobulin and immunoreceptor tyrosine inhibitor Motif (immunoreceptor tyrosine-based inhibitiory motif, ITIM) domain T cell immunoreceptor (T cell immunoreceptor with Ig and ITIM domains, TIGIT), etc., can inhibit T cell pairs after binding to the corresponding ligand molecules on the target cell surface. The killing of target cells, thus it is named after the immunization inspection checkpoint molecule or the checkpoint molecule (checkpoint molecule). As immunologists deepen their understanding of T cell functions and regulatory mechanisms, these inhibitory molecules have increasingly become a hot spot in clinical immunotherapy translational research.

PD-1, or CD279, is a cell surface type 1 transmembrane protein encoded by the PDCD1 gene. It belongs to the immunoglobulin superfamily and is expressed on T cells and pre-B cells. The cytoplasmic region of PD-1 contains ITIM, which can recruit phosphatase after activation to deliver the function of suppressing T cells. The ligands of PD-1 are PD-L1 and PD-L2, and the signal pathway for feedback regulation is: T cell receptor (TCR) on the T cell membrane is activated by the immunoreceptor tyrosine in the cytoplasmic region of CD3 Motif (immunoreceptor tyrosine-based activation motif, ITAM) sequentially activates Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase Cγ (PLCγ), and promotes transcription factors to activate T cell nuclear factors (nuclear factor of activated T cells, NFAT) phosphorylate and enter the nucleus, up-regulate PD-1 transcription and translation activity, and promote the expression of PD-1 molecules by activated T cells. After PD-1 binds to the ligand molecule PD-L1 on tumor cells, it can activate the Src homology 2 domain containing tyrosine phosphatase (Src homology 2 domain containing tyrosine phosphatase, through the ITIM domain of its intracellular segment). SHP2) inhibits the phosphorylation process of ZAP70/PLCγ, thereby reducing the production of cytokines, reducing the killing activity of target cells, and promoting the apoptosis of antigen-specific T cells. This “brake” system is a negative feedback regulation mechanism gradually established by the body in the long-term evolution process, which can stop the immune killing process in a timely manner and avoid excessive damage to normal tissues. To avoid and resist the killing of T cells, many kinds of tumor cells use this negative regulation “brake” molecule of the immune system. Tumor cells can express PD-L1 molecules at a high level on their own cell membranes, and when combined with PD-1 molecules on T cells, they can transmit inhibitory signals to T cells and cause T cells to lose their killing ability. Moreover, tumor cells can also secrete exosomes carrying PD-L1 molecules into the blood circulation, and reach remote sites through the bloodstream, and remotely inhibit T cells outside the tumor tissue, so that T cells have not yet reached the anti-tumor the local battlefield has already lost its lethality before.

Carrelizumab is a recombinant humanized anti-PD-1 monoclonal antibody, which has shown good efficacy in the immunotherapy of Hodgkin’s lymphoma and many other solid tumors. It shows its safety and effectiveness, but its efficiency is low. In the future, its combined application with chemotherapy, radiotherapy, immunotherapy and other anti-tumor therapies may further improve the efficacy.

To be continued in Part Three…

According to statistics from the World Health Organization in 2018, cancer is the main cause of human death. It shortens life expectancy and threatens human life and health. At present, the incidence and fatality rate of malignant tumors worldwide are increasing year by year. Anti-tumor treatment methods mainly include surgical treatment, chemotherapy, radiotherapy, immunotherapy, Chinese medicine treatment, etc. It is particularly important to find safe and effective therapeutic targets.

Molecular targeted therapy is also called “biological missile”. It designs corresponding therapeutic drugs for the identified carcinogenic sites at the cellular level. After the drugs enter the human body, they can selectively and specifically bind to the carcinogenic sites and exert their effects, leading to specific cancer cells. Sexual death without damaging normal tissue cells. The therapeutic effect is closely related to the characteristics of the drug itself and whether there is a molecular target and abnormal state of the targeted drug in the tumor. The choice of molecular targeted therapy relies on molecular pathological diagnosis. However, because pathological examination of tumor heterogeneity cannot obtain all tumor information, the efficacy of molecular targeted therapy is not necessarily consistent with the expected efficacy. The current targeted therapy sites for tumors mainly start from the tyrosine kinase receptor family, anti-angiogenesis and related intracellular and extracellular signaling pathways.

1. Trastuzumab for cancer treatment

Her2 is a transmembrane tyrosine kinase receptor protein in the epidermal growth factor receptor (EGFR) family. Its positive expression is closely related to the occurrence, development and prognosis of tumor cells. The molecular structure of Her2 includes intracellular domain, transmembrane domain and extracellular ligand binding domain, of which only the intracellular domain has tyrosine kinase activity. At present, no activated Her2 ligand has been found. Once Her2 is overexpressed, Her2 can form dimers, activate intracellular domains and phosphorylate at tyrosine kinase sites, activate downstream PI3K/Akt, MAPK pathways, and regulate tumor cell proliferation, differentiation, migration and apoptosis. Her2 oncogene is an oncogene that encodes Her2 protein on the q21 band of chromosome 17. The amplification of Her2 oncogene causes Her2 receptor overexpression, promotes the transformation of tumor cell phenotype, and promotes cell proliferation and tumorigenesis.

Trastuzumab (Trastuzumab, trade name Herceptin, herceptin) is a humanized monoclonal antibody that has become an important tumor-targeting drug. It mainly interacts with the Her2 oncogene expression product P185 on the tumor cell membrane. Protein binding produces anti-tumor activity. With the deepening of clinical research, Trastuzumab is used in the treatment of a variety of tumors, including breast cancer, ovarian cancer, gastric cancer, lung cancer, and kidney cancer. It has the characteristics of broad anti-tumor spectrum, definite curative effect and low side effects. However, its anti-tumor mechanism is still unclear.

At present, Trastuzumab has been widely used in the clinical treatment of Her2 positive tumors, but the anti-tumor mechanism found in research mainly includes the following points: 1) Inhibition of Her2 dimerization: Trastuzumab and Her2 The extracellular segment of Her2 specifically binds, blocking its formation of homodimers, inhibiting Her2 from binding to other ErbB receptors to form heterodimers, or blocking ligand-independent Her2/Her3 heterodimerization 2) Inhibit PI3K/AkT pathway: Trastuzumab can free the non-receptor tyrosine kinase Src from ErbB2 by acting on tumor cells, reduce the activity of Src kinase, and inhibit the phosphorylation of PTEN and transfer to the ion membrane It up-regulates its expression, inhibits the activation of PI3K, blocks the PI3K/AkT pathway, induces cell cycle G1 phase arrest and cell cycle-dependent kinase (CDK) inhibitor p27 kip1 accumulation and activation, and reduces tumor cell proliferation; 3) Inhibit the cleavage of the extracellular segment of ErbB2 and down-regulate its expression: Trastuzumab activates the receptor domain P95 connected to the cell membrane, induces endocytosis of ErbB2 and degrades it in the lysosome, and down-regulates the expression of ErbB2 4) Inhibition of angiogenesis: Trastuzumab can inhibit the production of vascular endothelial growth factor (vascular endothelial growth factor, VEGF), up-regulate the expression of thrombin sensitive protein 1, down-regulate blood vessel density, and inhibit tumor growth; 5) induce Immune response: The Fc region of Trastuzumab combines with natural killer cells (NKCs) to induce an immune response and reduce the production of VEGF; 6) induce antibody-dependent cytotoxicity and inhibit DNA damage repair.

Potential mechanisms for breast cancer treatment include: inhibiting the heterodimerization of Her2 and activating the cleavage of the extracellular segment of Her2, inducing the expression of p27 kip1; inhibiting PI3K signal, down-regulating Her2 and enhancing apoptosis regulation. Trastuzumab inhibits AP1510-induced Erk1/2 phosphorylation, blocks the combination of Shc and Her2 homodimers, regulates the proliferation of tumor cells, and has high therapeutic activity against breast cancer, while its adverse reactions are mild, mainly manifested as hypokalemia, thrombocytopenia and fatigue, and it has good tolerance to the treatment of advanced metastatic breast cancer. For decades, it has been found in clinical application that Trastuzumab can significantly improve the survival of breast cancer patients, but its treatment of patients still has certain limitations, such as neonatal and acquired tolerance, and blood-brain barrier. Among the patients who were initially treated with Trastuzumab, most of them developed significant drug resistance after 1 year of treatment. New adjuvant treatments such as Trastuzumab + paclitaxel and Trastuzumab + Pertuzumab were used clinically and achieved good therapeutic effects. Therefore, when breast cancer patients develop drug tolerance, the combination of drugs will provide breast cancer patients with new treatment hope.

To be continued in Part Two…