Alleviating Recombinant Tissue Plasminogen Activator-induced Hemorrhagic Transformation in Ischemic Stroke via Targeted Delivery of a Ferroptosis Inhibitor.

Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

Amphiphilic α-Peptoid-deoxynojirimycin Conjugate-based Multivalent Glycosidase Inhibitor for Hypoglycemic Effect and Fluorescence Imaging.

Multivalent glycosidase inhibitors based on 1-deoxynojirimycin derivatives against α-glucosidases have been rapidly developed. Nonetheless, the mechanism based on self-assembled multivalent glucosidase inhibitors in living systems needs to be further studied. It remains to be determined whether the self-assembly possesses sufficient stability to endure transit through the small intestine and subsequently bind to the glycosidases located therein. In this paper, two amphiphilic compounds, 1-deoxynojirimycin and α-peptoid conjugates (LP-4DNJ-3C and LP-4DNJ-6C), were designed. Their self-assembling behaviors, multivalent α-glucosidase inhibition effect, and fluorescence imaging on living organs were studied. LP-4DNJ-6C exhibited better multivalent α-glucosidase inhibition activities in vitro. Moreover, the self-assembly of LP-4DNJ-6C could effectively form a complex with Nile red. The complex showed fluorescence quenching effect upon binding with α-glucosidases and exhibited potent fluorescence imaging in the small intestine. This result suggests that a multivalent hypoglycemic effect achieved through self-assembly in the intestine is a viable approach, enabling the rational design of multivalent hypoglycemic drugs.

Nucleolus imaging based on naphthalimide derivatives.

Nucleolus was an important cellular organelle. The abnormal morphology and number of the nucleolus have been considered as diagnostic biomarkers for some human diseases. However, the imaging agent based on nucleolus was limited. In this manuscript, a series of nucleolar fluorescent probes based on naphthalimide derivatives (NI-1 âˆ¼ NI-5) had been designed and synthesized. NI-1 âˆ¼ NI-5 could penetrate cell membranes and nuclear membranes, achieve clear nucleolar staining in living cells. These results suggested that the presence of amino groups on the side chains of naphthalimide backbone could enhance the targeting to the cell nucleolus. In addition, the molecular docking results showed that NI-1 âˆ¼ NI-5 formed hydrogen bonds and hydrophobic interactions with RNA, and exhibited enhanced fluorescence upon binding with RNA. These results will provide favorable support for the diagnosis and treatment of nucleolus-related diseases in the future.

Supramolecular Integration of Multifunctional Nanomaterial by Mannose-Decorated Azocalixarene with Ginsenoside Rb1 for Synergistic Therapy of Rheumatoid Arthritis.

The complexity and progressive nature of diseases require the exploitation of multifunctional materials. However, introducing a function inevitably increases the complexity of materials, which complicates preparation and decreases reproducibility. Herein, we report a supramolecular integration of multifunctional nanomaterials based on mannose-modified azocalix[4]arene (ManAC4A) and ginsenoside Rb1 (Rb1), which showed advances of simplicity and reproducibility. ManAC4A possesses reactive oxygen species (ROS) scavenging capacity and hypoxia-responsiveness, together with macrophage-targeting and induction functionality. Collectively, the Rb1@ManAC4A assembly simply prepared by two components is integrated with multifunction, including triple targeting (ELVIS targeting, macrophage-targeting, and hypoxia-targeted release) and triple therapy (ROS scavenging, macrophage polarization, and the anti-inflammatory effect of Rb1). The spontaneous assembly and recognition of ManAC4A, with its precise structure and molecular weight, facilitated the simple and straightforward preparation of Rb1@ManAC4A, leading to excellent batch consistency. Progress in simplicity and reproducibility, as directed by this research, will catalyze the clinical translation of multifunctional materials.

Calixarene-based cryoprotectants for ice recrystallization inhibition and cell cryopreservation.

The development of new cryoprotectants for cryopreservation of cells has attracted considerable interest. Herein, five calixarene-based CPAs (SC4A, S-S-C4A, S-SO2-C4A, SBAC4A, and CAC4A) were developed, and their IRI activity, DIS property and cryoprotective effect were studied. SBAC4A with a sulphobetaine zwitterion and SC4A with sulfo group modification possessed better cryoprotective effects than the other calixarene-based CPAs, especially for SBAC4A with the enhanced cell viabilities of 16.16 ± 1.78%, 12.60 ± 1.15% and 14.90 ± 1.66% against MCF-7, hucMSCs and A549 cells, respectively. This result provides a supramolecular principle for developing novel CPAs with consideration of the factors of hydrogen bonding, the macromolecular crowding principle and the three-dimensional (3D) structure.

Triple targeting host-guest drug delivery system based on lactose-modified azocalix[4]arene for tumor ablation.

Host-guest drug delivery systems (HGDDSs) have been studied in an effort to modify the characteristics of therapeutic agents through noncovalent interactions, reduce toxic side effects and improve therapeutic effects. However, it is still an important task to continuously improve the targeting ability of HGDDSs, which is conducive to the development of precision medicine. Herein, we utilize the lactose-modified azocalix[4]arene (LacAC4A) as a triple targeting drug carrier customized for antitumor purposes. LacAC4A integrates three targeting features, passive targeting through the enhancing permeability and retention effect, active targeting by the interactions of lactose and the asialoglycoprotein receptors on the surface of tumor cells, and stimuli-responsive targeting via the reduction of the azo group under a hypoxia microenvironment. After loading doxorubicin (DOX) in LacAC4A, the supramolecular nanoformulation DOX@LacAC4A clearly showed the effective suppression of tumor growth through in vivo experiments. LacAC4A can achieve effective targeting, rapid release, and improve drug bioavailability. This design principle will provide a new material for drug delivery systems.

Fluorescence sensing and glycosidase inhibition effect of multivalent glycosidase inhibitors based on Naphthalimide-deoxynojirimycin conjugates.

Synthetic glycoconjugates as chemical probes have been widely developed for the detection of glycosidase enzymes. However, the binding interactions between iminosugar derivatives and glycosidases were limited, especially for the binding interactions between multivalent glycosidase inhibitors and α-glycosidases. In this paper, three naphthalimide-DNJ conjugates were synthesized. Furthermore, the binding interactions and glycosidase inhibition effects of them were investigated. It was found that the strong binding interactions of multivalent glycosidase inhibitors with enzymes were related to the efficient inhibitory activity against glycosidase. Moreover, the lengths of the chain between DNJ moieties and the triazole ring for the naphthalimide-DNJ conjugates influenced the self-assembly properties, binding interactions and glycosidase inhibition activities with multisource glycosidases. Compound 13 with six carbons between the DNJ moiety and triazole ring showed the stronger binding interactions and better glycosidase inhibition activities against α-mannosidase (jack bean) and α-glucosidase (aspergillus niger). In addition, compound 13 showed an effective PBG inhibition effect in mice with 51.18 % decrease in blood glucose at 30 min. This result opens a way for detection of multivalent glycosidase inhibition effect by a fluorescent sensing method.

Lactose azocalixarene drug delivery system for the treatment of multidrug-resistant pseudomonas aeruginosa infected diabetic ulcer.

Diabetic wound is one of the most intractable chronic wounds that is prone to bacterial infection. Hypoxia is an important feature in its microenvironment. However, it is challenging for antimicrobial therapy to directly apply the existing hypoxia-responsive drug delivery systems due to the active targeting deficiency and the biofilm obstacle. Herein, we customizes a hypoxia-responsive carrier, lactose-modified azocalix[4]arene (LacAC4A) with the ability to actively target and inhibit biofilm. By loading ciprofloxacin (Cip), the resultant supramolecular nanoformulation Cip@LacAC4A demonstrates enhanced antibacterial efficacy resulting from both the increased drug accumulation and the controlled release at the site of infection. When applied on diabetic wounds together with multidrug-resistant Pseudomonas aeruginosa infection in vivo, Cip@LacAC4A induces definitely less inflammatory infiltration than free Cip, which translates into high wound healing performance. Importantly, such design principle provides a direction for developing antimicrobial drug delivery systems.

Multivalent glucosidase inhibitors based on perylene bisimide and iminosugar conjugates.

Although multivalent glucosidase inhibitors based on iminosugars have shown enhanced inhibition activity, an effective way to improve their hypoglycemic effect in vivo, is still in infancy and needs further development. In this paper, PBI-5DNJ and PBI-6DNJ, with three or four DNJ moieties respectively conjugated at the bay position were synthesized. PBI-6DNJ evidenced stronger π-π stacking interactions and, when self-assembled, a smaller size than that of PBI-5DNJ. It was found that PBI-6DNJ exhibited superior α-glucosidases (from mice) inhibition activity (Ki = 0.14 ± 0.007 µM) in vitro than that (Ki = 0.31 ± 0.01) of PBI-5DNJ and in vivo hypoglycemic effects in mice models. PBI-6DNJ possessed good hypoglycemic effects with the percentages of PBG levels of 40.40 ± 3.33% and 39.23 ± 4.84% at a dose of 2.0 mg/kg after 15 min and 30 min of administration, respectively. In terms of measuring percentage decrease of PBG level per DNJ unit, PBI-6DNJ displayed a 2.1-fold enhancement than miglitol, demonstrating a consistency between in vitro and in vivo experiments. This paves the way to the connection between in vivo hypoglycemic potency and in vitro glucosidase inhibition assay, leading to reliable and simplified assessment of hypoglycemic potency determination, and opening a basic understanding of the design of multivalent glucosidase inhibitors.

Macrocycle molecule-based cryoprotectants for ice recrystallization inhibition and cell cryopreservation.

Cyclodextrin-based cryoprotectants were developed. α-TMCD, which can be easily put into large-scale production, showed enhanced cell viabilities of 19.97 ± 0.78%, 13.93 ± 4.46% and 19.10 ± 0.95% against GES-1, hucMSCs and A549 cells. Moreover, the viable cells observed by light microscope imaging showed that the enhanced hucMSC cell number percentage of α-TMCD was 103.2%. An α-TMCD-DMSO-based CPA exhibited an enhanced cryoprotective effect by a mechanism of DMSO-enhanced cell penetrating effect and α-TMCD-DMSO synergistically enhanced IMA ability. α-TMCD exhibited potential for the discovery of macrocycle-molecule-based cryoprotectants.

Synthesis, Renal Clearance, and Photothermal Therapy Based on the Self-Assembly of a Nanomedicine Consisting of Quaterrylene Bisimide and Glycocluster Conjugates.

Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation → self-regulating the aggregate size through the renal filtration thresholds → reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.

Correction: Synthesis, self-aggregation and cryopreservation effects of perylene bisimide-glycopeptide conjugates.

Correction for 'Synthesis, self-aggregation and cryopreservation effects of perylene bisimide-glycopeptide conjugates' by Xu He et al., Chem. Commun., 2021, DOI: 10.1039/d1cc03835d.

Synthesis, self-aggregation and cryopreservation effects of perylene bisimide-glycopeptide conjugates.

Three perylene bisimide-glycopeptide conjugates (PBI-AFF-Man, PBI-AFF-Glu and PBI-AFF-Gal) were synthesized, which showed moderate activity in the control of ice crystal growth. Furthermore, the cellular cryopreservation effects of PBI-AFF-Man, PBI-AFF-Glu and PBI-AFF-Gal showed enhancements in cell viabilities, especially for PBI-AFF-Glu with values of 22.77 ± 3.33% (HeLa cells), 19.43 ± 1.90% (A549 cells) and 16.63 ± 1.76% (GES-1 cells) at a dose of 1.0 mg mL-1. This work will help guide the development of self-assembled cryoprotectants.

Nucleus-targeting imaging and enhanced cytotoxicity based on naphthalimide derivatives.

Organelles possess critical biological effects in cellular processes. However, the relationship between organelle targeting and antitumour activity is a challenging issue. In this paper, a number of amide/acylhydrazine modified naphthalimide derivatives were designed and synthesized. Interestingly, amide modified naphthalimide derivatives NI-A-NH and NI-C-NH with (R)-piperdine and (S)-pyrrolidine functionalization exhibited enhanced cytotoxicity compared with acylhydrazine modified derivatives NI-A-2NH and NI-C-2NH. However, acylhydrazine modified derivatives NI-B-2NH and NI-D-2NH with (S)-piperdine and achiral piperdine conjugates possessed better cytotoxicity than NI-B-NH and NI-D-NH with amide modifications. Fluorescence imaging, DNA binding interactions and cell cycle analyses were further completed to clarify that the nucleus-targeting effects showed enhanced cytotoxic activity, strong DNA binding and the blocking of cells in S phase. These results provide a preliminary theoretical basis for the further design of organelle-targeting antitumour drugs.

Universal colorful staining of cancer tissues and normal tissues for histological diagnosis.

The versatility of multicolor imaging of human tissues based on staining with perylene monoimide-mannose conjugates PMI-Man and co-staining with PMI-Man and eosin (P&E) was investigated for human cancer and normal tissues. Staining with PMI-Man or co-staining with PMI-Man and eosin showed a perfect histological morphology both in confocal fluorescence microscopy and light microscopy. This approach provided a universal colorful staining method for cancer tissues and normal tissues.

Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide-deoxynojirimycin Conjugates.

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

Selective sensing of DNA and live/dead cells and histological imaging based on a perylene derivative.

A mannose-modified perylene monoimide derivative PMI-Man was developed, which shows highly selective binding to double-stranded DNA molecules, potent live/dead cell imaging, and histological imaging via both confocal and light microscopies. This approach can be used to develop a universal colorful staining method for human tissues for both confocal and light microscopies.

Antitumour properties based on the self-assembly of camptothecin and carbamoylmannose conjugates.

Camptothecin (CPT) and its analogues show potent antitumour activity. However, poor water solubility and severe side effects have restricted their applications in clinical practice. In this paper, a novel self-assembly based on camptothecin and carbamoylmannose conjugates (CPT-Man) was constructed. The self-assembly increased the water solubility of camptothecin to 0.64 mg/ml and antitumour activity. Moreover, CPT-Man could induce obvious cancer cell apoptosis. This work provides a new approach for exploring carbohydrate-modified antitumour properties by self-assembled CPT drugs.

Effective Renal Clearance and Photothermal Therapy of a Cyclodextrin-Modified Quaterrylene Derivative.

Metabolic clearance of drugs from the body is a key element for future clinical applications. Compared with the liver-bile metabolic route, the renal-urinary route is the most desirable and efficient clearance pathway for practical use in clinical trials and can effectively decrease the long-term risk of unpredictable intracellular catabolism and the potential toxicity to normal organs. However, renal clearable photothermal therapy (PTT) agents were limited. In this paper, a permethyl-ß-cyclodextrin-modified quaterrylene bisimide derivative (QDI-CD) was developed. QDI-CD as a biocompatible molecule could effectively be cleared with the renal clearance efficiency of (67.00 ± 2.37)% at 24 h by the renal-urinary route when administered by tail vein injection. Importantly, the structure of QDI-CD in urine after metabolism does not change. Furthermore, QDI-CD, as a potent photoacoustic and photothermal agent, could effectively be enriched in tumor tissue after 4 h of injection and showed the effective PTT in mice. This work developed a potent organic PTT agent with good renal clearance from the body and with promise for future clinical applications.

Cooling-Induced NIR Emission Enhancement and Targeting Fluorescence Imaging of Biperylene Monoimide and Glycodendrimer Conjugates.

Under high concentrations, strong pressure, and low temperature, fluorophores usually exhibit the fluorescence quenching phenomenon. Of significance, the development of aggregation-induced emission (AIE) and pressure-induced emission (PIE) fluorophores has perfectly prevented fluorescence quenching under high concentrations and strong pressure. However, cooling-induced fluorescence quenching in water is still an urgent problem. In this paper, cooling-induced emission (CIE) enhancement based on a biperylene monoimide (BPMI) derivative, BPMI-18Lac, with a conjugated lactose-based glycodendrimer was developed. BPMI-18Lac, as a non-AIE molecule, exhibited the CIE phenomenon with a fluorescent intensity increasing 7-fold when the temperature decreased from 80 to -40 °C. The mechanism was due to the inhibition of the intramolecular electron interactions between the perylene monoimide moieties linked by the C-C single bond. In addition, BPMI-18Lac, as a multivalent glycodendrimer, showed selective fluorescence imaging for HepG 2 cells through the ASGP receptor on the cell surface. Importantly, this work developed a water-soluble CIE molecule for potential application below freezing temperature.