Polymer Conjugates Research Articles

Attenuating Metabolic Competition of Tumor Cells for Favoring the Nutritional Demand of Immune Cells by a Branched Polymeric Drug Delivery System.

Tumor cells are dominant in the nutritional competition in the tumor microenvironment, and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the antitumor therapeutic effect. Herein, a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells are reported. Compared with the control nanoparticles prepared from its linear counterpart, the branched-conjugate-based nanoparticles can more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieves an enhanced antitumor effect. The work presents a promising approach for targeting metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers.

Long-Acting Insulin-Zwitterionic Polymer Conjugate Mitigates Hypoglycemia.

Insulin, a main medication to control glycemia of type 1 and advanced type 2 diabetes, faces problems of a short half-life and poor stability during its clinical use. Zwitterionic polymer shows unique properties of antifouling and low immunogenicity. Here, we have synthesized a new insulin-zwitterionic polymer conjugate (INS-PMPC) through grafting-from strategy by controlled radical polymerization. Apart from showing excellent stability upon mechanical agitation, the resulting INS-PMPC conjugate provided over 20 h of glycemic control due to improved pharmacokinetics in diabetic mice with one single subcutaneous injection. Most importantly, this insulin-zwitterionic polymer conjugate significantly decreases the incidence of hypoglycemia.

Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature.

The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(α,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against Pseudomonas aeruginosa was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.

The Evolution of SNAP-Tag Labels.

The conjugation of proteins with synthetic molecules can be conducted in many different ways. In this Perspective, we focus on tag-based techniques and specifically on the SNAP-tag technology. The SNAP-tag technology makes use of a fusion protein between a protein of interest and an enzyme tag that enables the actual conjugation reaction. The SNAP-tag is based on the O6-alkylguanine-DNA alkyltransferase (AGT) enzyme and is optimized to react selectively with O6-benzylguanine (BG) substrates. BG-containing dye derivatives have frequently been used to introduce a fluorescent tag to a specific protein. We believe that the site-specific conjugation of polymers to proteins can significantly benefit from the SNAP-tag technology. Especially, polymers synthesized via reversible deactivation radical polymerization allow for the facile introduction of a BG end group to enable SNAP-tag conjugation.

Bioactive Glass-Ceramic Scaffolds Coated with Hyaluronic Acid-Fatty Acid Conjugates: A Feasibility Study.

Promoting bone healing is a key challenge in our society that can be tackled by developing new implantable biomaterials provided with regenerative properties. In this work, the coating of three-dimensional porous glass-derived scaffolds with hyaluronic acid (HA)-fatty acids was investigated for the first time. The starting scaffolds, based on bioactive silicate glass, were produced by foam replication followed by sintering; then, HA-palmitate and HA-oleate conjugate coatings were deposited on the scaffold struts through a dipping procedure. FT-IR analysis confirmed the successful deposition of the coatings on the surface and struts of the scaffolds, the foam-like architecture of which was maintained as assessed by SEM investigations. The in vitro bioactivity of the HA-fatty-acid-coated scaffolds was studied by immersion tests in simulated body fluid and the subsequent evaluation of hydroxyapatite formation. The deposition of the polymeric coating did not inhibit the apatite-forming ability of scaffolds, as revealed by the formation of nanostructured hydroxyapatite agglomerates 48 h from immersion. These promising results motivate further investigation of these novel bioactive systems, which are expected to combine the bone-bonding properties of the glass with the wound-healing promotion carried out by the polymeric conjugates.

Recent advances in access to overcome cancer drug resistance by nanocarrier drug delivery system.

Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.

Corrigendum to “Conjugation of a zwitterionic polymer with dimethyl chains to lipase significantly increases the enzyme activity and stability” [Chinese J. Chem. Eng. 47 (2022) 48–53

Corrigendum to “Conjugation of a zwitterionic polymer with dimethyl chains to lipase significantly increases the enzyme activity and stability” [Chinese J. Chem. Eng. 47 (2022) 48–53

How Key Alterations of Mesoporous Silica Nanoparticles Affect Anti-Lung Cancer Therapy? A Comprehensive Review of the Literature.

In 2020, there were 2.21 million new instances of lung cancer, making it the top cause of mortality globally, responsible for close to 10 million deaths. The physicochemical problems of chemotherapy drugs are the primary challenge that now causes a drug's low effectiveness. Solubility is a physicochemical factor that has a significant impact on a drug's biopharmaceutical properties, starting with the rate at which it dissolves and extending through how well it is absorbed and bioavailable. One of the most well-known methods for addressing a drug's solubility is mesoporous silica, which has undergone excellent development due to the conjugation of polymers and ligands that increase its effectiveness. However, there are still very few papers addressing the success of this discovery, particularly those addressing its molecular pharmaceutics and mechanism. Our study's objectives were to explore and summarize the effects of targeting mediator on drug development using mesoporous silica with and without functionalized polymer. We specifically focused on highlighting the molecular pharmaceutics and mechanism in this study's innovative findings. Journals from the Scopus, PubMed, and Google Scholar databases that were released during the last ten years were used to compile this review. According to inclusion and exclusion standards adjusted. This improved approach produced very impressive results, a very significant change in the characteristics of mesoporous silica that can affect effectiveness. Mesoporous silica approaches have the capacity to greatly enhance a drug's physicochemical issues, boost therapeutic efficacy, and acquire superb features.

Size-switchable polymer-based nanomedicines in the advanced therapy of rheumatoid arthritis.

Chronic inflammatory diseases such as rheumatoid arthritis represent a substantial socio-economic impact and have a high prevalence in the modern world. Nano-sized polymer therapeutics have shown suitable characteristics for becoming the next generation of anti-inflammatory nanomedicines. Here, we present biocompatible and stimuli-sensitive N-(2-hydroxypropyl)methacrylamide based polymer conjugates with the anti-inflammatory drug dexamethasone (DEX), which has been tailored for prolonged blood circulation, enhanced inflammatory site accumulation, site-specific drug release and subsequent elimination of the carrier via urine excretion. The hydrodynamic size of novel polymer-DEX nanomedicine was adjusted to prolong its blood circulation whilst maintaining the renal excretability of the polymer carrier after drug release in inflamed tissue. The therapeutic efficacy of the studied polymer nanomedicines was evaluated in a model of dissipated chronic arthritis, i.e. collagen II-induced arthritis, in mice. The pH-sensitive drug attachment enabled enhanced blood circulation with minimal systemic drug release, as well as rapid drug activation in affected joints. Importantly, unlike free DEX, the polymer nanomedicines were able to diminish joint inflammation and arthritis-induced bone damage - even at a reduced dosing regimen - as evaluated by micro computed tomography (micro-CT).

Hypoxia alleviating platinum(IV)/chlorin e6-based combination chemotherapeutic-photodynamic nanomedicine for oropharyngeal carcinoma

Hypoxia is an important pathological hallmark of the tumor microenvironment, associated with metabolic alterations, cell proliferation, aggressiveness, metastasis, and therapy resistance in cancers. Hypoxia impedes the outcome of photodynamic therapy (PDT), which is largely dependent on molecular oxygen to generate cytotoxic 1O2. Here, a near-infrared light activatable, oxygen-generating nanomicellar PDT-chemotherapy system (mPPCPN Ms) constituted of amphiphilic mPEG-PLA, photosensitizer Ce6, and tetravalent platinum prodrug Pt(IV)-diazide was developed for oral squamous cell carcinoma. The polymer conjugate self-assemble to nanosize (115±2.35nm) micelles, which, upon irradiation (660nm laser), activated Ce6, and photodecomposed to produce cytotoxic Pt(II), azidyl radical, and molecular oxygen. The strategically fabricated PDT-chemotherapy produced a strong antitumor response in vitro using oral squamous cell carcinoma and in vivo in oral cancer-xenografted mouse models, revealing its significant potential in chemo-photodynamic combination therapy with the benefit of reversing hypoxia.

Polymer modification of SARS-CoV-2 spike protein impacts its ability to bind key receptor

The global spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) has caused the loss of many human lives and severe economic losses. SARS-CoV-2 mediates its infection in humans via the spike glycoprotein. The receptor binding domain of the SARS-CoV-2 spike protein binds to its cognate receptor, angiotensin converting enzyme-2 (ACE2) to initiate viral entry. In this study, we examine how polymer modification of the spike protein receptor binding domain impacts binding to ACE2. The horseradish peroxidase conjugated receptor binding domain was modified with a range of polymers including hydrophilic N,N-dimethylacrylamide, hydrophobic N-isopropylacrylamide, cationic 3-(N,N-dimethylamino)propylacrylamide, and anionic 2-acrylamido-2-methylpropane sulfonic acid polymers. The effect of polymer chain length was observed using N,N-dimethylacrylamide polymers with degrees of polymerization of 5, 10 and 25. Polymer conjugation of the receptor binding domain significantly reduced the interaction with ACE2 protein, as determined by an enzyme-linked immunosorbent assay. Stability analysis showed that these conjugates remained highly stable even after seven days incubation at physiological temperature. Hence, this study provides a detailed view of the effect specific type of modification using a library of polymers with different functionalities in interrupting RBD-ACE2 interaction.

Peptide–Polymer Conjugates: A Promising Therapeutic Solution for Drug-Resistant Bacteria

By 2050, it is estimated that 10 million people will die of drug-resistant bacterial infection caused by antibiotic abuse. Antimicrobial peptide (AMP) is widely used to prevent such circumstances, for the positively charged AMPs can kill drug-resistant bacteria by destroying negatively charged bacterial cell membrane, and has excellent antibacterial efficiency and low drug resistance. However, due to the defects in low in vivo stability, easy degradation, and certain cytotoxicity, its practical clinical application is limited. The emergence of peptide–polymer conjugates (PPC) helps AMPs overcome these shortcomings. By combining with functional polymers, the positive charge of AMPs is partially shielded, and its stability and water solubility are improved, so as to prolong the in vivo circulation time of AMPs and reduce its cytotoxicity. At the same time, the self-assembly ability of PPC enables it to assemble into different nanostructures to undertake specific antibacterial tasks. At present, PPC is mainly used in wound dressing, bone tissue repair, antibacterial coating of medical devices, nerve repair, tumor treatment, and oral health maintenance. In this study, we summarize the structure, synthesis methods, and the clinical applications of PPC, so as to present the current challenges and discuss the future prospects of antibacterial therapeutic materials.

Pharmaceutical Functionalization of Monomeric Ionic Liquid for the Preparation of Ionic Graft Polymer Conjugates

Polymerizable choline-based ionic liquid (IL), i.e., [2-(methacryloyloxy)ethyl]-trimethylammonium (TMAMA/Cl¯), was functionalized by an ion exchange reaction with pharmaceutical anions, i.e., cloxacillin (CLX¯) and fusidate (FUS¯), as the antibacterial agents. The modified biocompatible IL monomers (TMAMA/CLX¯, TMAMA/FUS¯) were copolymerized with methyl methacrylate (MMA) to prepare the graft copolymers (19-50 mol% of TMAMA units) serving as the drug (co)delivery systems. The in vitro drug release, which was driven by the exchange reaction of the pharmaceutical anions to phosphate ones in PBS medium, was observed for 44% of CLX¯ (2.7 μg/mL) and 53% of FUS¯ (3.6 μg/mL) in the single systems. Similar amounts of released drugs were detected for the dual system, i.e., 41% of CLX¯ (2.2 μg/mL) and 33% of FUS¯ (2.0 μg/mL). The investigated drug ionic polymer conjugates were examined for their cytotoxicity by MTT test, showing a low toxic effect against human bronchial epithelial cells (BEAS-2B) and normal human dermal fibroblasts (NHDF) as the normal cell lines. The satisfactory drug contents and the release profiles attained for the well-defined graft polymers with ionically bonded pharmaceuticals in the side chains make them promising drug carriers in both separate and combined drug delivery systems.

Degradation of Polymer-Drug Conjugate Nanoparticles Based on Lactic and Itaconic Acid.

Tuberculosis (TB) is still a significant threat to human health. A promising solution is engineering nanoparticulate drug carriers to deliver anti-TB molecules. Itaconic acid (ITA) potentially has anti-TB activity; however, its incorporation in nanoparticles (NP) is challenging. Here we show an approach for preparing polymer-ITA conjugate NPs and a methodology for investigating the NP degradation and ITA release mechanism. The conjugate was synthesized by the two-directional growing of polylactic acid (PLA) chains, followed by capping their extremities with ITA. The poly(lactate)-itaconate PLA-ITA was then used to formulate NPs. The degradation and drug release processes of the polymer conjugate NPs were studied qualitatively and quantitatively. The molecular structures of released species were characterized by using liquid NMR spectroscopy and mass spectrometry. We discovered a complex NP hydrolysis process forming diverse oligomers, as well as monomeric lactic acid (LA) and drug ITA. The slow degradation process led to a low release of free drugs, although raising the pH from 5.3 to 7.4 induced a slight increase in the amounts of released products. TEM images showed that bulk erosion is likely to play the primary role in the degradation of PLA-ITA NPs. The overall results and methodology can be of interest for understanding the mechanisms of NP degradation and drug release of this new polymer-drug conjugate system.

Traceless pH-Sensitive Antibody Conjugation Inspired by Citraconic Anhydride.

We introduce a pH-sensitive amide bond, inspired by citraconic anhydride, for the reversible conjugation of polymers to the lysine residues of proteins and antibodies. The pH sensitivity arises from a conformation lock at the end of the polymer, which we introduce by means of a Diels-Alder reaction, that positions a carboxylic acid close to the amide after conjugation occurs. The amide is stable over weeks at pH 7.4 but sensitive to hydrolysis at pH 5.5 and below, returning the amine to its original state. The pH sensitivity can be tuned by positioning secondary amide groups nearby. We use this approach to PEGylate an antibody to human serum albumin at high dilution and demonstrate successful recovery of the activity after hydrolysis at pH 5.5. These results offer a convenient and traceless approach to protein and antibody functionalization.

Polymer-Covered Copper Catalysts Alter the Reaction Pathway of the Electrochemical CO2 Reduction Reaction.

The electrochemical CO2 reduction reaction (CO2RR) has attracted considerable attention recently due to the potential conversion of atmospheric CO2 into useful organic products by utilizing electricity from renewable energy sources. However, the selective formation of desired products only via CO2RR has been elusive due to the presence of a myriad of competing reaction pathways, thus calling for effective strategies controlling the reaction coordinates. The control of binding energies of the reaction intermediate, such as *CO, is pivotal to manipulating reaction pathways, and various attempts have been made to accomplish this goal. Herein, we introduce recent endeavors to increase the catalytic selectivity of Cu-based catalysts by surface modification with polymer coating, which can change the local pH, hydrophilicity/hydrophobicity, reaction concentration, etc. The polymer conjugation also contributed to the enhanced electrocatalytic stability of Cu-based catalysts during the CO2RR. We also point to the remaining challenges and provide perspectives on the further development of Cu-polymer hybrid catalysts for the practical CO2RR.

Tailoring Protein-Polymer Conjugates as Efficient Artificial Enzymes for Aqueous Asymmetric Aldol Reactions.

Artificial enzymes are becoming a powerful toolbox for selective organic syntheses. Herein, we first propose an advanced artificial enzyme by polymeric modularity as an efficient aldolase mimic for aqueous asymmetric aldol reactions. Based on an in-depth understanding of the aldolase reaction mechanism and our previous work, we demonstrate the modular design of protein-polymer conjugates by co-incorporating l-proline and styrene onto a noncatalytic protein scaffold with a high degree of controllability. The tailored conjugates exhibited remarkable catalytic performance toward the aqueous asymmetric aldol reaction of p-nitrobenzaldehyde and cyclohexanone, achieving 94% conversion and excellent selectivity (95/5 diastereoselectivity, 98% enantiomeric excess). In addition, this artificial enzyme showed high tolerance against extreme conditions (e.g., wide pH range, high temperature) and could be reused for more than four times without significant loss of reactivity. Experiments have shown that the artificial enzyme displayed broad specificity for various aldehydes.

Tumor microenvironment and redox dual stimuli-responsive polymeric nanoparticles for the effective cisplatin-based cancer chemotherapy

The serious side effects of cisplatin hindered its clinical application and the nanotechnology might be the potential strategy to address the limitation. However, rapid clearance in the blood circulation and ineffective controlled drug release from nanocarriers hamper the therapeutic efficacy of the nano-delivery system. We constructed a tumor microenvironment and redox dual stimuli-responsive nano-delivery system PEG-c-(BPEI-SS-Pt) by cross-linking the disulfide-containing polymeric conjugate BPEI-SS-Pt with the dialdehyde group-modified PEG2000 via Schiff base. After optimized the cross-linking time, 72 h was selected to get the nano-delivery system. 1H NMR and drug release assays showed that under the acidic tumor microenvironment (pH 6.5–6.8), the Schiff base can be broken and detached the PEG cross-linked outer shells, displaying the capability to release the drugs with a sequential pH- and redox-responsive manner. Moreover, PEG-c-(BPEI-SS-Pt) showed more effective anti-tumor therapeutic efficacy in vivo with no significant side effects when compared with the drug of cisplatin used in the clinic. This strategy highlights a promising platform with the dual stimuli-responsive profile to achieve better therapeutic efficacy and minor side effects for platinum-based chemotherapy.

Folate receptor-targeted PLGA-PEG nanoparticles for enhancing the activity of genistein in ovarian cancer

Genistein (GEN), a natural isoflavone possesses a wide range of pharmacological properties and nutraceutical applications. GEN has been studied for its anticancer activity against different types of cancers, but its use in clinical practice is limited due to its low water solubility, rapid metabolism and excretion, lack of cancer cell targeting and poor bioavailability. In the present study, we investigated folate receptor-targeted and PEGylated poly(lactide-co-glycolide) nanoparticles (PLGA-PEG-FA NPs) containing GEN for targeted delivery to ovarian cancer cells. PLGA-PEG and PLGA-PEG-FA polymer conjugates were synthesized and characterized. Nano-precipitation method was employed for the fabrication of NPs of PLGA, PLGA-PEG and PLGA-PEG-FA containing GEN. GEN containing PLGA-PEG and PLGA-PEG-FA NPs prepared were small (104.17 ± 1.61 and 125.41 ± 3.11 nm, respectively) and exhibited sustained release of GEN for around six days. Folate-decorated PLGA-PEG NPs showed increased cellular uptake in comparison to non-targeted PLGA-PEG NPs. The GEN containing PLGA-PEG-FA NPs showed superior anticancer activity than non-targeted PLGA and PLGA-PEG NPs in folate receptor-overexpressing ovarian cancer cell line, SKOV-3. The IC50 of GEN, GEN encapsulated NPs of PLGA, PLGA-PEG and PLGA-PEG-FA were 51.48, 26.70, 23.43 and 11.98 µg/ml, respectively. Folate-targeted PLGA nanoparticles could be developed for potential target-specific delivery of GEN in the treatment of ovarian cancer.

Tumor-Targeting Polymer–Drug Conjugate for Liver Cancer Treatment In Vitro

Bufalin (buf) has poor solubility in aqueous solution, poor tumor targeting, and many non-specific toxic and side effects. The advantages of high-molecular-weight polymer conjugates are that they can improve the water solubility of buf, prolong plasma half-life, and reduce non-specific toxicity. A novel water-soluble polymer-drug conjugate with buf and fluorescein pendants was prepared by the combination of reversible addition-fragmentation transfer (RAFT) polymerization and click chemistry. Its anticancer performance and cellular uptake behavior against liver cancer were investigated in vitro. The polymer-buf conjugates exhibit controlled release and tumor-targeting capabilities, showing promise for clinical applications.