Aptamer-Assisted Blockade of the Immune Suppressor Sialic Acid-Binding Immunoglobulin-Like Lectin-15 for Cancer Immunotherapy

The percentage of low response and adaptive resistance to current antibody-based immune checkpoint blockade (ICB) therapy requires the development of novel immunotherapy strategies. Here, we developed an aptamer-assisted immune checkpoint blockade (Ap-ICB) against sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15), a novel immune suppressor broadly upregulated on cancer cells and tumor infiltrating myeloid cells, which is mutually exclusive of programmed cell death ligand 1 (PD-L1). Using protein aptamer selection, we identified WXY3 aptamer with high affinity against Siglec-15 protein/Siglec-15 positive cells. We demonstrated that WXY3 aptamer rescued antigen-specific T cell responses in vitro and in vivo. Importantly, the WXY3 Ap-ICB against Siglec-15 amplified anti-tumor immunity in the tumor microenvironment and inhibited tumor growth/metastasis in syngeneic mouse model, which may result from enhanced macrophage and T cell functionality. In addition, by using aptamer-based spherical nucleic acids, we developed a synergetic ICB strategy of multivalent binding and steric hindrance, which further improves the in vivo anti-tumor effect. Taken together, our results support Ap-ICB targeted Siglec-15 as a potential strategy for normalization cancer immunotherapy.     

Molecularly Imprinted Nanobeacons Redirect Innate Immune Killing towards Triple Negative Breast Cancer

Harnessing innate immunity is an appealing strategy for cancer treatment. Herein, we report a new strategy called molecularly imprinted nanobeacons (MINBs) for redirecting innate immune killing towards triple-negative breast cancer (TNBC). The MINBs were molecularly imprinted nanoparticles with the N-epitope of glycoprotein nonmetastatic B (GPNMB) as the template and grafted with plentiful fluorescein moieties as the hapten. The MINBs could tag the TNBC cells via binding with GPNMB and thereby provide navigation for recruiting hapten-specific antibodies. The gathered antibodies could further trigger effective Fc-domain-mediated immune killing towards the tagged cancer cells. In vivo experiments showed that the TNBC growth was significantly inhibited after MINBs treatment by intravenous injection as compared with control groups. This study not only opens a new access for redirecting innate immunity towards TNBC but also paves the way for innate immunity-based therapy of other diseases.     

A Semiconducting Iron-Chelating Nano-immunomodulator for Specific and Sensitized Sono-metallo-immunotherapy of Cancer

Sono-immunotherapy holds great potential for deep tumor inhibition; however, smart sono-therapeutic agents to simultaneously eliminate ‘domestic’ tumor cells and regulate the ‘community’ tumor immune microenvironment have rarely been developed. Herein, we report a spatiotemporally controllable semiconducting iron-chelated nano-metallomodulator (SINM) for hypersensitive sono-metallo-immunotherapy of cancer. SINM consists of a semiconducting polymer (SP) backbone chelating iron ions (Fe³⁺) with thiophene-based Schiff base structure, and a hydrophilic side chain. Upon accumulation in tumors after systemic administration, SINM specifically arouses ferroptosis and M1 macrophage polarization due to its response toward the tumor redox environment; meanwhile, the chelation of Fe³⁺ enhances the sono-sensitizing effect of SPs, leading to enhanced generation of reactive oxygen species for immunogenic cell death. Such combined sonodynamic metallo-immunotherapy of SINM efficiently ablates deep tumor and spatiotemporally regulates immunophenotypes.     

Activatable Semiconducting Polymer Pro-nanomodulators for Deep-Tissue Sono-immunotherapy of Orthotopic Pancreatic Cancer

Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen (¹O₂)-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of ¹O₂ under US treatment, even in a deep-tissue depth up to 12 cm. The generated ¹O₂ not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the ¹O₂-cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.     

Organic-Platinum Hybrids for Covalent Binding of G-Quadruplexes: Structural Basis and Application to Cancer Immunotherapy

G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L¹-cispt and L¹-transpt , with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L¹-transpt -MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L¹-cispt- and L¹-transpt- mediated genomic dysfunction could activate the retinoic acid-induced gene I (RIG-I) pathway and induce immunogenic cell death (ICD). The use of L¹-cispt/L¹-transpt- treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4-trageting drug design and their potential in immunotherapy.     

Natural Polyphenols as Immunomodulators to Rescue Immune Response Homeostasis: Quercetin as a Research Model against Severe COVID-19

The COVID-19 pandemic is caused by SARS-CoV-2 and is leading to the worst health crisis of this century. It emerged in China during late 2019 and rapidly spread all over the world, producing a broad spectrum of clinical disease severity, ranging from asymptomatic infection to death (4.3 million victims so far). Consequently, the scientific research is devoted to investigating the mechanisms of COVID-19 pathogenesis to both identify specific therapeutic drugs and develop vaccines. Although immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, new understanding has emerged about the innate and adaptive immune responses elicited in SARS-CoV-2 infection, which are mainly focused on the dysregulated inflammatory response in severe COVID-19. Polyphenols are naturally occurring products with immunomodulatory activity, playing a relevant role in reducing inflammation and preventing the onset of serious chronic diseases. Mainly based on data collected before the appearance of SARS-CoV-2, polyphenols have been recently suggested as promising agents to fight COVID-19, and some clinical trials have already been approved with polyphenols to treat COVID-19. The aim of this review is to analyze and discuss the in vitro and in vivo research on the immunomodulatory activity of quercetin as a research model of polyphenols, focusing on research that addresses issues related to the dysregulated immune response in severe COVID-19. From this analysis, it emerges that although encouraging data are present, they are still insufficient to recommend polyphenols as potential immunomodulatory agents against COVID-19.     

高分子材料调控肿瘤免疫微环境的研究进展

随着肿瘤免疫疗法在临床应用取得巨大突破,通过抗肿瘤免疫反应提高抗肿瘤疗效的治疗方式受到了广泛的关注.然而,肿瘤组织存在复杂的免疫抑制性微环境,严重限制了部分免疫疗法的效果.长期以来,高分子材料作为重要的药物递送载体受到广泛关注,但是其在调控肿瘤免疫微环境的功能及应用方面尚未引起足够的重视.在本文中,我们一方面介绍了肿瘤组织形成免疫抑制性微环境的成因,如肿瘤组织存在多种免疫抑制性细胞,如调节性T细胞(Tregs)、髓系来源抑制性细胞(MDSCs)和肿瘤相关巨噬细胞(TAMs)等,以及免疫细胞、肿瘤细胞等分泌的大量细胞因子、趋化因子、代谢产物等.另一方面,重点介绍了近年来高分子材料作为载体递送免疫调节分子或发挥自身免疫调节功能,调控或逆转免疫抑制性微环境的策略和典型代表,证明了高分子材料在调控肿瘤免疫微环境,改善肿瘤治疗效果方面的巨大潜力.     

老药新用抗击新冠肺炎*

新冠肺炎疫情爆发以来,临床上通过老药新用的策略发展小分子药物,以用于治疗新冠肺炎。在短时间内迅速从抗病毒、抗炎药物中发现能够用于新冠治疗的药物,如洛匹那韦/利托那韦、磷酸氯喹等。结合几款典型的药物,浅析它们在抗击新冠肺炎中的应用。     

Plant Polysaccharides Modulate Immune Function via the Gut Microbiome and May Have Potential in COVID-19 Therapy

Plant polysaccharides can increase the number and variety of beneficial bacteria in the gut and produce a variety of active substances, including short-chain fatty acids (SCFAs). Gut microbes and their specific metabolites have the effects of promoting anti-inflammatory activity, enhancing the intestinal barrier, and activating and regulating immune cells, which are beneficial for improving immunity. A strong immune system reduces inflammation caused by external viruses and other pathogens. Coronavirus disease 2019 (COVID-19) is still spreading globally, and patients with COVID-19 often have intestinal disease and weakened immune systems. This article mainly evaluates how polysaccharides in plants can improve the immune system barrier by improving the intestinal microecological balance, which may have potential in the prevention and treatment of COVID-19.     

Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (M^pro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski’s filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as M^pro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.     

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.     

Alginate‐Based Microcapsules with a Molecule Recognition Linker and Photosensitizer for the Combined Cancer Treatment

A reactive template method was used to fabricate alginate‐based hydrogel microcapsules. The uniform and well‐dispersed hydrogel capsules have a high drug loading capacity. After they are coated by a folate‐linked lipid mixture on the surface, the capsules possess higher cell uptake efficiency by the molecule recognition between folate and the folate‐receptor overexpressed by the cancer cells. Moreover, in this bioconjugate, the lipid could remarkably reduce the release rate of hydrophilic doxorubicin from the hydrogel microcapsules and encapsulate the hydrophobic photosensitizer hypocrellin B. The biointerfaced capsules could be used as drug carriers for combined treatment against cancer cell proliferation in vitro; this was much more effective than chemotherapy or photodynamic therapy alone.     

Re‐engineering the Immune Response to Metastatic Cancer: Antibody‐Recruiting Small Molecules Targeting the Urokinase Receptor

Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer.     

Injectable Polypeptide Hydrogel Depot System for Assessment of the Immune Response–Inducing Efficacy of Sustained Antigen Release Alone

Vaccines typically contain an antigen, delivery system (vehicle), and adjuvant, all of which contribute to inducing a potent immune response. Consequently, design of new vaccines is difficult, because the contributions and interactions of these components are difficult to distinguish. Here, it is aimed to develop an easy‐to‐use, non‐immunogenic, injectable depot system for sustained antigen release that will be suitable for assessing the efficacy of prolonged antigen exposure per se for inducing an immune response. This should mimic real‐life infections. Recombinant elastin‐like polypeptides with periodic cysteine residues (cELPs) are selected, which reportedly show little or no immunogenicity, as carriers and tetanus toxoid (Ttd) as an antigen. After subcutaneous injection of the mixture, cELP rapidly forms a disulfide cross‐linked hydrogel in situ, within which Ttd is physically incorporated, affording a biodegradable antigen depot. A series of Ttd‐containing hydrogels is examined. A single injection induces high levels of tetanus antibody with high avidity for at least 20 weeks in mice. The chain length of cELP proves critical, whereas differences in hydrophobicity has little effect, although hydrophilic cELPs are more rapidly biodegraded. This system's ability to distinguish the contribution of sustained antigen release to antibody induction should be helpful for rational design of next‐generation vaccines.     

The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19

Hemostasis disorders play an important role in the pathogenesis, clinical manifestations, and outcome of COVID-19. First of all, the hemostasis system suffers due to a complicated and severe course of COVID-19. A significant number of COVID-19 patients develop signs of hypercoagulability, thrombocytopenia, and hyperfibrinolysis. Patients with severe COVID-19 have a tendency toward thrombotic complications in the venous and arterial systems, which is the leading cause of death in this disease. Despite the success achieved in the treatment of SARS-CoV-2, the search for new effective anticoagulants, thrombolytics, and fibrinolytics, as well as their optimal dose strategies, continues to be relevant. The wide therapeutic potential of seaweed sulfated polysaccharides (PSs), including anticoagulant, thrombolytic, and fibrinolytic activities, opens up new possibilities for their study in experimental and clinical trials. These natural compounds can be important complementary drugs for the recovery from hemostasis disorders due to their natural origin, safety, and low cost compared to synthetic drugs. In this review, the authors analyze possible pathophysiological mechanisms involved in the hemostasis disorders observed in the pathological progression of COVID-19, and also focus the attention of researchers on seaweed PSs as potential drugs aimed to correction these disorders in COVID-19 patients. Modern literature data on the anticoagulant, antithrombotic, and fibrinolytic activities of seaweed PSs are presented, depending on their structural features (content and position of sulfate groups on the main chain of PSs, molecular weight, monosaccharide composition and type of glycosidic bonds, the degree of PS chain branching, etc.). The mechanisms of PS action on the hemostasis system and the issues of oral bioavailability of PSs, important for their clinical use as oral anticoagulant and antithrombotic agents, are considered. The combination of the anticoagulant, thrombolytic, and fibrinolytic properties, along with low toxicity and relative cheapness of production, open up prospects for the clinical use of PSs as alternative sources of new anticoagulant and antithrombotic compounds. However, further investigation and clinical trials are needed to confirm their efficacy.     

Molecular docking identification for the efficacy of natural limonoids against COVID-19 virus main protease

COVID-19 pandemic is the biggest public health problem of the century so far.The main protease (Mpro) is one of the main enzymes studied as a pharmacological target. In this context, the present work aimed to perform a virtual screening of possible inhibitors against the enzyme Mpro, having limonoids as the main object of research as supposed inhibitors. Molecular docking simulations indicated that limonoids have an affinity to complex with M-pro.However, Limonine and Nimoliciol showed nonspecific and low affinity interactions. In conclusion, Limonoids are substances of natural origin that can be used in the study of new pharmacological tools designed to combat and understand COVID-19.     

Targeted Degradation of PD-L1 and Activation of the STING Pathway by Carbon-Dot-Based PROTACs for Cancer Immunotherapy

Proteolysis targeting chimeras (PROTACs) technology is an emerging approach to degrade disease-associated proteins. Here, we report carbon-dot (CD)-based PROTACs (CDTACs) that degrade membrane proteins via the ubiquitin-proteasome system. CDTACs can bind to programmed cell death ligand 1 (PD-L1), recruit cereblon (CRBN) to induce PD-L1 ubiquitination, and degrade them with proteasomes. Fasting-mimicking diet (FMD) is also used to enhance the cellular uptake and proteasome activity. More than 99 % or 90 % of PD-L1 in CT26 or B16-F10 tumor cells can be degraded by CDTACs, respectively. Furthermore, CDTACs can activate the stimulator of interferon genes (STING) pathway to trigger immune responses. Thus, CDTACs with FMD treatment effectively inhibit the growth of CT26 and B16-F10 tumors. Compared with small-molecule-based PROTACs, CDTACs offer several advantages, such as efficient membrane protein degradation, targeted tumor accumulation, immune system activation, and in vivo detection.     

化学教学新课堂：科学抗疫中的化学知识

As the break out of COVID-19 epidemic, the prevention and control work was consequently carried out. Chemistry plays an important role in the white war. The structure of mask contains the knowledge of interfacial chemistry. The material of mask encompasses the knowledge of polymer chemistry. Nucleic acid test and COVID-19 vaccine research need the knowledge of biological chemistry. The sanitizers involve the knowledge of inorganic and organic chemistry. The knowledge of physical chemistry takes effect in daily hand washing with soap. Each drug against COVID-19 virus was a complex organic compound. All the above things can be taken as appropriate examples in chemistry teaching to display the charm of chemistry. Meanwhile, these examples help students to realize that chemistry works as a vital part in our lives and therefore active their motivation to study chemistry well.     

Evaluation of a potential prognostic parameter for the inflammatory status in COVID-19 patients: The inflammatory protein ratio

C-reactive protein (CRP), fibrinogen, and d -dimer are determined in the human plasma of 2745 hospitalized patients with and without coronavirus disease 2019 (COVID-19) by automated-latex enhanced immunoassay and immuno-turbidimetric assay. SARS-COV-2 RNA qualitative test, real time polymerase chain reaction (RT-PCR) based, is performed in nasopharyngeal swabs to confirm those with SARS-COV-2 positivity. Furthermore, serum proteins are separated and quantified in all the patients by serum protein electrophoresis (SPE). A new SPE parameter, inflammatory protein ratio (IPR), is elaborated for the first time by a mathematical equation that considers the albumin, α1-globulin, and α2-globulin. IPR normal reference range (10.7%–28.3%) is calculated considering the normal reference range of albumin, α1-globulin, and α2-globulin obtained for controls. Analysis of variance (ANOVA), Pearson's, Kruskal–Wallis, and Spearman's tests application show that IPR significantly correlates with direct proportionality with d -dimer, CRP, and fibrinogen. Significant (p < 0.001) increase of these parameters, IPR included, is detected in COVID-19 patients only. Our results show that IPR is more specific for monitoring inflammatory status thanks to its correlation with the only three serum proteins involved in inflammation: albumin, α1-globulin, and α2-globulin. Furthermore, IPR can simplify the interpretation of SPE results about inflammatory status, being of unique value compared to the six-serum protein classes separately presented in the typical SPE clinical reports.     

Ecofriendly and sustainable Sargassum spp.-based system for the removal of highly used drugs during the COVID-19 pandemic

Analgesic consumption increased significantly during the COVID-19 pandemic. A high concentration of this kind of drug is discarded in the urine, reaching the effluents of rivers, lakes, and seas. These medicines have brought serious problems for the flora and, especially, the ecosystems’ fauna. This paper presents the results of removing diclofenac, ibuprofen, and paracetamol in an aqueous solution, using Sargassum spp. from the Caribbean coast. The study consisted of mixing each drug in an aqueous solution with functionalized Sargassum spp in a container under constant agitation. Therefore, this work represents an alternative to solve two of the biggest problems in recent years; first, the reduction of the overpopulation of sargassum through its use for the remediation of the environment. Second is the removal of drug waste used excessively during the COVID-19 pandemic. Liquid samples of the solution were taken at intervals of 10 min and analyzed by fluorescence to determine the concentration of the drug.The sorption capacity for diclofenac, ibuprofen, and paracetamol was 2.46, 2.08, and 1.41 μg/g, corresponding to 98 %, 84 %, and 54 % of removal, respectively. The removal of the three drugs was notably favored by increasing the temperature to 30 and 40 °C, reaching efficiencies close to 100 %. Moreover, the system maintains its effectiveness at various pH values. In addition, the Sargassum used can be reused for up to three cycles without reducing its removal capacity. The wide diversity of organic compounds favors the biosorption of drugs, removing them through various kinetic mechanisms. On the other hand, the Sargassum used in the drugs removal was analyzed by X-ray diffraction, FTIR spectroscopy, TGA analysis, and scanning electron microscopy before and after removal. The results showed an evident modification in the structure and morphology of the algae and demonstrated the presence of the biosorbed drugs. Therefore, this system is sustainable, simple, economical, environmentally friendly, highly efficient, and scalable at a domestic and industrial level that can be used for aquatic remediation environments.