Synergistic dual cell therapy for atherosclerosis regression: ROS-responsive Bio-liposomes co-loaded with Geniposide and Emodin.

The development of nanomaterials for delivering natural compounds has emerged as a promising approach for atherosclerosis therapy. However, premature drug release remains a challenge. Here, we present a ROS-responsive biomimetic nanocomplex co-loaded with Geniposide (GP) and Emodin (EM) in nanoliposome particles (LP NPs) for targeted atherosclerosis therapy. The nanocomplex, hybridized with the macrophage membrane (Møm), effectively evades immune system clearance and targets atherosclerotic plaques. A modified thioketal (TK) system responds to ROS-rich plaque regions, triggering controlled drug release. In vitro, the nanocomplex inhibits endothelial cell apoptosis and macrophage lipid accumulation, restores endothelial cell function, and promotes cholesterol effluxion. In vivo, it targets ROS-rich atherosclerotic plaques, reducing plaque area ROS levels and restoring endothelial cell function, consequently promoting cholesterol outflow. Our study demonstrates that ROS-responsive biomimetic nanocomplexes co-delivering GP and EM exert a synergistic effect against endothelial cell apoptosis and lipid deposition in macrophages, offering a promising dual-cell therapy modality for atherosclerosis regression.

Protective effect of carbon dots as antioxidants on intestinal inflammation by regulating oxidative stress and gut microbiota in nematodes and mouse models.

Inflammatory bowel disease (IBD) is a recurrent chronic colitis disease with increasing incidence and prevalence year by year. The single efficacy and significant side effects of traditional IBD treatment drugs have promoted the flourishing development of new drugs. Inspired by many health benefits of carbon dots (CDs) based nanomedicine in biomedical applications, a metal-free carbon dots (CP-CDs) was synthesized from citric acid and polyethylene polyamine to treat colitis. Oxidative stress tests at the cellular and nematode levels demonstrated CP-CDs have good antioxidant effects, while the toxicity of CP-CDs to cells and nematodes is low. CP-CDs were further applied to dextran sodium sulfate (DSS)-induced colitis in mice models, and it was found that CP-CDs can reduce the disease activity index (DAI) score of colon tissue and restore the intestinal barrier. Further, the anti-colitis mechanisms of CP-CDs were explored, one of which is to regulate intestinal oxidative stress in inflammatory mice, further reducing the expression of inflammatory cytokines, and thus alleviating colitis. Notably, 16S rRNA sequence analysis showed that the abundance of beneficial bacteria (Ligilactobacillus and Enterorhabdus) in the intestinal tract increased, while that of harmful bacteria (unclassified_Clostridia_UCG_014) decreased after CP-CDs treatment, indicating that CP-CDs rebalancing the gut microbiota destroyed by DSS is another important mechanism. In short, these non-toxic carbon dots not only have the potential for multi-factor combined relief of colitis but also offer an alternative therapy medicine for patients suffering from IBD.

Dual-emission carbon dots for ratiometric fluorescence sensing of thiabendazole in fruits.

Quantitative determination of pesticides in fruits and vegetables is essential for human healths. Herein, a new dual-emission carbon dots with high fluorescence stability at a pH range of 4-10 and a temperature range of 0-60 °C was synthesized. And a novel ratiometric fluorescence probe was proposed to detect thiabendazole (TBZ) residue with a wide linear range (0-1000 µM) and low detection limit (0.15 µM). The emission at 512 nm exhibited a special "turn-off" fluorescence sensing of TBZ due to internal filter effect, while that at 361 nm barely changed and worked as reference. Furthermore, the ratiometric fluorescence strategy was successfully applied for determining TBZ in fruits with good recoveries (96.73%-111.17 %, 93.29%-120.78 % and 96.28%-100.57 %, respectively). Notably, the constructed ratiometric fluorescence probe had comparable accuracy to HPLC in detecting unknown concentrations of TBZ in pear juice, demonstrating dual-emission carbon dots possess wide and promising applicability for fluorescence sensing pesticides in the future.

Molecular identification and safety assessment of the potential probiotic strain Bacillus paralicheniformis HMPM220325 isolated from artisanal fruit dairy products.

Bacillus probiotics exhibit considerable economic potential owing to their heightened resilience to external stressors and relatively lower costs related to production and preservation. Although Bacillus paralicheniformis has been acknowledged as a plant-promoting bacterium for a long time, understanding its potential as a probiotic is still in its nascent stages. In this study, the safety and probiotic characteristics of a strain of HMPM220325, isolated from artisanal fruit dairy products, were examined through whole-genome sequencing and phenotypic analysis. The whole genome of HMPM220325 was analyzed for antimicrobial resistance genes, pathogenicity factors, and genes associated with probiotic traits including stress resistance, spore formation, gut adhesion, competitive exclusion of pathogens, bacteriocin expression, and carbohydrate metabolism related to prebiotic utilization. Also, wet lab experiments were conducted for the characterization of probiotics. The identification of the organism as B. paralicheniformis was verified. Its safety was assessed through in silico analysis, the haemolytic activity test, and the acute oral toxicity test. B. paralicheniformis HMPM220325 demonstrated its ability to survive in the pH range of 4-10 and bile salt concentrations of 0-0.9% (w/v), tolerate temperatures between 20 and 60 °C, and exhibit a robust antioxidant capacity. Moreover, B. paralicheniformis HMPM220325 demonstrated a moderate level of hydrophobicity, had the ability to form biofilms, achieved a self-aggregation rate of 51.77 ± 1.01% within 6 hours, and successfully colonized the mouse intestine for a duration of up to 17 days. Additionally, the genome of B. paralicheniformis HMPM220325 contains three gene clusters associated with the biosynthesis of bacteriocins and exhibits co-aggregation with Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella enterica serovar Typhimurium. The findings of the genomic analysis align with those obtained from the experimental investigation, thereby substantiating the potential of B. paralicheniformis HMPM220325 as a probiotic suitable for incorporation in dairy functional foods and feed applications.

Quantification and characterization of microplastics in farmland soils of Jiangsu Province, East China.

The soil ecosystem plays a significant role in the dynamics of microplastics. Qualitative and quantitative analyses of microplastics in six farmland plots from the cities of Nanjing, Suzhou, and Xuzhou were conducted by using laser infrared imaging system (LDIR). The results showed that the abundance of microplastics in farmland soils in Jiangsu Province ranged from 667-9333 items/kg, and the difference between the abundance of microplastics in soils from open-field cultivation and greenhouse farming was not significant. The vertical distribution characteristics showed that the abundance of microplastic decreased significantly with the increase of soil depth. However, there was no significant difference in particle size between top soil (0-5 cm) and deep soil (10-20 cm). Fragments were the most common microplastic form in soil samples (94.6%), with polyvinyl chloride (PVC) being the main polymer type, followed by polyethylene terephthalate (PET). Compared with previous studies conducted in China, the abundance of microplastics in farmland soils in Jiangsu Province was at moderate level but was notably higher than other places within the Yangtze River Delta region. The conclusions drawn from this paper provided important reference data for future assessment of microplastic pollution in agricultural fields. Furthermore, they establish a fundamental groundwork for understanding the migration patterns of MPs in soil environments.

Synthesis, properties and mechanism of carbon dots-based nano-antibacterial materials.

Antibiotics play an important role in the treatment of diseases, but bacterial resistance caused by their widespread and unreasonable use has become an urgent problem in clinical treatment. With the rapid advancement of nanoscience and nanotechnology, the development of nanomedicine has been transformed into a new approach to the problem of bacterial resistance. As a new type of carbon-based nanomaterial, carbon dots (CDs) have attracted the interest of antibacterial researchers due to their ease of preparation, amphiphilicity, facile surface functionalization, and excellent optical properties, among other properties. This article reviewed the synthesis methods and properties of various CDs and their composites in order to highlight the advancements in the field of CDs-based antibacterial agents. Then we focused on the relationship between the principal properties of CDs and the antibacterial mechanism, including the following: (1) the physical damage caused by the small size, amphiphilicity, and surface charge of CDs. (2) Photogenerated electron transfer characteristics of CDs that produce reactive oxygen species (ROS) in themselves or in other compounds. The ability of ROS to oxidize can lead to the lipid peroxidation of cell membranes, as well as damage proteins and DNA. (3) The nano-enzyme properties of CDs can catalyze reactions that generate ROS. (4) Synergistic antibacterial effect of CDs and antibiotics or other nanocomposites. Finally, we look forward to the challenges that CDs-based nanocomposites face in practical antibacterial applications and propose corresponding solutions to further expand the application potential of nanomaterials in the treatment of infectious diseases, particularly drug-resistant bacterial infections.

Evolocumab loaded Bio-Liposomes for efficient atherosclerosis therapy.

PCSK9, which is closely related to atherosclerosis, is significantly expressed in vascular smooth muscle cells (VSMCs). Moreover, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) mediated phenotypic transformation, abnormal proliferation, and migration of VSMCs play key roles in accelerating atherosclerosis. In this study, by utilizing the significant advantages of nano-materials, a biomimetic nanoliposome loading with Evolocumab (Evol), a PCSK9 inhibitor, was designed to alleviate atherosclerosis. In vitro results showed that (Lipo + M)@E NPs up-regulated the levels of α-SMA and Vimentin, while inhibiting the expression of OPN, which finally result in the inhibition of the phenotypic transition, excessive proliferation, and migration of VSMCs. In addition, the long circulation, excellent targeting, and accumulation performance of (Lipo + M)@E NPs significantly decreased the expression of PCSK9 in serum and VSMCs within the plaque of ApoE-/- mice.

Acute coronary syndrome with severe atherosclerotic and hyperthyroidism: A case report.

BACKGROUND: Acute coronary syndrome (ACS) encompasses a spectrum of cardiovascular emergencies arising from the obstruction of coronary artery blood flow and acute myocardial ischemia. Recent studies have revealed that thyroid function is closely related to ACS. However, only a few reports of thyrotoxicosis-induced ACS with severe atherosclerosis have been reported. CASE SUMMARY: A 33-year-old man, who had a history of hyperthyroidism without taking any antithyroid drugs and no history of coronary heart disease, experienced neck pain with occasional heart palpitations starting 3 mo prior that were aggravated after an activity. As the symptoms worsened at 21 d prior, he went to a hospital for treatment. The electrocardiogram examination showed a multilead ST segment elevation and pathological Q waves. Based on these findings and his symptoms, the patient was diagnosed with a suspected myocardial infarction and transferred to our hospital on July 2, 2020. He was diagnosed with a rare case of ACS due to coronary artery atherosclerosis in the anterior descending artery complicated by hyperthyroidism. A paclitaxel-coated drug balloon was used for treatment to avoid the use of metal stents, thus reducing the time of antiplatelet therapy and facilitating the continued treatment of hyperthyroidism. The 9-mo follow-up showed favorable results. CONCLUSION: This case highlights that atherosclerosis is a cause of ACS that cannot be ignored even in a patient with hyperthyroidism.

Nanoparticles of a New Small-Molecule P-Selectin Inhibitor Attenuate Thrombosis, Inflammation, and Tumor Growth in Two Animal Models.

PURPOSE: To assess whether the newly designed small-molecule oral P-selectin inhibitor 3S-1,2,3,4-tetrahydro-ß-carboline-3-methyl aspartyl ester (THCMA) as a nanomedicine enhances antithrombosis, anti-inflammation, and antitumor activity more than the clinical trial drug PSI-697. METHODS: THCMA was designed as an amphiphile containing pharmacophores of PSI-697. Its nanofeatures were explored with TEM, SEM, Tyndall effect, ζ-potential, FT-ICR-MS, and NOESY 2D 1H NMR. The P-selectin inhibitory effect of THCMA was demonstrated with molecular docking, ultraviolet (UV) spectra, and competitive ELISA. In vivo and in vitro assays - anti-arterial thrombosis, anti-venous thrombosis, anti-inflammation, antitumor growth, anti-platelet aggregation, rat-tail bleeding time, anticoagulation index, soluble P-selectin (sP-selectin) expression, and serum TNFα expression - were performed to explore bioactivity and potential mechanisms. Water solubility of THCMA was measured using UV-absorption spectra. RESULTS: THCMA self-assembled into nanorings of approximately 100 nm in diameter. Its water solubility was about 1,030-fold that of PSI-697. THCMA exhibited more potent P-selectin inhibitory effect than PSI-697. The oral efficacy of THCMA was 100-fold that of PSI-697 in inhibiting arterial and venous thrombosis and tenfold in inhibiting inflammation. THCMA inhibited thrombosis at a dose that produces no coagulation disorders and no bleeding risk. THCMA exhibited enhanced antitumor activity over PSI-697 without systemic chemotherapy toxicity. THCMA significantly inhibited platelet aggregation in vitro and downregulated the expression levels of serum sP-selectin and TNFα in vivo. CONCLUSION: A new small-molecule P-selectin inhibitor, THCMA, has been successfully designed as a nanomedicine with largely enhanced oral efficacy compared to the clinical trial drug PSI-697, and thus might be developed for the oral treatment of arterial thrombosis, venous thrombosis, inflammation, and cancer-associated thrombosis.

In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database.

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson-Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

Chlorin e6-loaded sonosensitive magnetic nanoliposomes conjugated with the magnetic field for enhancing anti-tumor effect of sonodynamic therapy.

In sonodynamic therapy (SDT), when Chlorin e6 (Ce6) accumulates in tumor tissues, its anti-tumor effect can be achieved by ultrasound activation. To increase the local drug concentration of Ce6 in tumor cells, we had established a novel drug delivery system, Ce6-loaded sonosensitive magnetic nanoliposome (Ce6/SML), which realized the targeting delivery by the external magnetic field. It was worth mentioning that the targeting release of Ce6/SML and the activation on Ce6 could be achieved simultaneously by ultrasound of SDT. In our study, after Ce6 was loaded into the sonosensitive magnetic nanoliposome (SML), the values of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in vitro and in vivo were determined, indicating the activation on Ce6 of ultrasound. The delivery system also displayed the tumor-targeting ability and anti-tumor activity, which associated with the determined tumor growth and expression levels of angiogenin (ANG), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α). In conclusion, the Ce6/SML-SDT-Targeted delivery system could effectively enhance the anti-tumor activity of SDT and had a great potential application for the treatment of malignant tumors located in deep tissues.

Discovery of DEBIC to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis.

Arterial thrombosis is one of the major complications of cancer and can seriously worsen the prognosis of the patients. These clinical findings encouraged this paper to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis. By designing and docking 12 derivatives of bisindole- 2-carboxylic acids into the active sites of P-selectin and d(CGATCG)2 9 derivatives were assigned to receive in vivo anti-tumor assay, and finally provided dimethyl 2,2'-[(2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]diacetate (DEBIC) to receive assays. DEBIC intercalated DNA and inhibited proliferation of tumor cells but not non-tumor cells. It slowed tumor growth of S180 mice at a dose of 0.36 µmol/kg, and slowed tumor growth of A549 bearing BABL/C mice at a dose of 8.9 µmol/kg. DEBIC was also found to inhibit arterial thrombosis by down regulating P-selectin effectively at a dose of 0.36 µmol/kg.

Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA.

BACKGROUND: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance. METHODS: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4-tetrahydroisoquino-line-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor. RESULTS: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose dependently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity was1670 folds of that of aspirin. CONCLUSION: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis.

Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent.

The impact of soluble P-selectin on tumor growth, thrombosis and inflammation has been individually documented. Whether the down-regulation of P-selectin expression can simultaneously slow the tumor growth, inhibit the thrombosis and attenuate the inflammatory response remains unknown. In this context, (2'S,5'S)- tetrahydropyrazino[1',2':1,6]-di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1',4'-dione (THPDTPI) was designed as an inhibitor of P-selectin. The suitable docking of THPDTPI towards the active site of P-selectin, the significant down-regulation of THPDTPI to P-selectin expression, and the direct action of THPDTPI on P-selectin suggest that P-selectin could be a target of THPDTPI. In vivo THPDTPI possesses the anti-tumor activity, the anti-thrombotic activity and the anti-inflammatory activity. This implies that targeting P-selectin is of essential importance for this triple activity. The minimal effective doses of THPDTPI inhibiting the tumor growth, the rat arterial thrombosis and the mouse ear edema are 0.01 µmol/kg, 0.1 µmol/kg and 0.001 µmol/kg, respectively. Atomic force microscopy images and FT-MS spectra showed that the adhesion of THPDTPI onto the surfaces of the platelets may be the first step of P-selectin targeting. Besides, the dependence of the triple action of THPDTPI inhibiting the tumor growth, the thrombosis and the inflammation on the decrease of the soluble P-selectin led to the correlation of the soluble P-selectin with the serum TNF-α and serum IL-8.

Hydroxycamptothecin liposomes based on thermal and magnetic dual-responsive system: preparation, in vitro and in vivo antitumor activity, microdialysis-based tumor pharmacokinetics.

Due to the absence of lactone form of hydroxycamptothecin, the commercially available hydroxycamptothecin injection exhibits inefficient therapeutic effects. In this study, we constructed a novel delivery system (thermosensitive magnetic liposomes) that protects lactone form of hydroxycamptothecin from blood or water. After hydroxycamptothecin was loaded into the thermosensitive magnetic liposome (HCPT/TML), its in vitro and in vivo antitumor activity and microdialysis-based tumour pharmacokinetics were determined. The results demonstrated that HCPT/TMLs possessed favourable physicochemical features and significant cytotoxicity against the Huh-7 cells in vitro. In the in vivo antitumor study and tumour pharmacokinetics, HCPT/TMLs displayed effective targeting delivery and antitumor effects, which corresponded to the determined hydroxycamptothecin concentration in tumour tissue. In conclusion, this thermal and magnetic dual-responsive system can efficiently deliver hydroxycamptothecin to tumour tissue and has great potential application in cancer treatment.

IQCA-TAVV: To explore the effect of P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 on deep venous thrombosis.

Deep vein thrombosis (DVT) associates with considerable morbidity, functional disability and mortality. Due to the lack of suitable inhibitor the correlation of various factors in DVT onset remains unknown. In this context we analyzed the structure of anti-platelet aggregation agent, P-selectin down-regulator, GPIIb/IIIa down-regulator and anti-inflammatory agent, thereby designed N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)- Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) as an inhibitor of DVT to receive evaluations. The docking predicted that IQCA-TAVV can target P-selectin and GPIIb/IIIa. The UV showed that IQCA-TAVV can act on P-selectin and GPIIb/IIIa. ELISA indicated that IQCA-TAVV concentration dependently inhibited activated platelets to express P-selectin and GPIIb/IIIa, and the minimal effective concentration was 1 nM. IC50 of IQCA-TAVV against platelet aggregation induced by arachidonic acid, adenosine diphosphate and platelet activating factor fell within a range of 0.13 nM to 0.30 nM. In vivo IQCA-TAVV dose-dependently inhibited venous thrombosis and the minimal effective dose was 1 nmol/kg. On ear edema model the anti-inflammation activity of 10 nmol/kg IQCA-TAVV equaled that of 1.1mmol/kg aspirin. The concentration of IL-2, IL-6 and IL-8 in the serum of the ear edema mice were also significantly decreased by 10 nmol/kg IQCA-TAVV. Even at 1 µmol/kg of dose IQCA-TAVV still did not injure the kidney, the liver, and the nerves of healthy mice. Thereby IQCA-TAVV depicts a relationship of three levels (inhibiting platelet activation, targeting externalized membrane receptor, decreasing serum inflammatory factor) for the down-regulation of P-selectin, GPIIb/IIIa, IL-2, IL-6 and IL-8 in DVT.

ATIQCTPC targeting MMP-9: a key step to slowing primary tumor growth and inhibiting metastasis of lewis lung carcinoma in vivo.

In this study we docked (6S)-3-acetyl-4-oxo-N-(2-(3,4,5,6-zetrahydroxytetrahydro-2H-pyran-2-carboxamido)ethyl)-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carbo-xamide (ATIQCTPC) towards the active site of MMP-9, and showed that ATIQCTPC was able to effectively decrease the level of MMP-9 in the serum and the primary tumor of Lewis lung carcinoma (LLC) implanted C57BL/6 mice. As a MMP-9 inhibitor, ATIQCTPC inhibited the metastasis of LLC, and slowed the growth of the primary tumor of LLC implanted C57BL/6 in mice. The activities of ATIQCTPC to inhibit the ear edema and to decrease the serum levels of TNF-α and IL-8 of the mice treated with xylene were explored. The minimal effective dose of ATIQCTPC that can inhibit the primary tumour growth, prevent the metastasis of LLC and reduce the inflammatory response was 0.01 λmol/kg. The minimal effective dose of ATIQCTPC inhibiting tumour growth and metastasis was 100-fold lower than that of (S)-3-acetyl- 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC, parent compound). The minimal effective dose of ATIQCTPC inhibiting inflammation was 110-fold lower than that of aspirin. These superiorities reflected the rationality of ATIQCTPC design. The safety of the therapy was explained by 1 λmol/kg of ATIQCTPC did not injure the kidney, the liver and the heart of the treated inflammation mice.

ATIQCTPC: a nanomedicine capable of targeting tumor and blocking thrombosis in vivo.

To overcome the harmful side effects, low tolerance, and undesirable outcomes of the anticancer drugs, we used ethane-1,2-diamine to bridge antitumoral (S)-3-acetyl-4-oxo-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC) and tumor-targeting d-glucuronic acid, thereby providing (6S)-3-acetyl-4-oxo-N-(2-(3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxamido)ethyl)-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxamide (ATIQCTPC). Atomic force microscopy images visualized, that in serum, ATIQCTPC formed particles of height <81 nm. These particles effectively avoided phagocytosis of macrophages and were stable in blood circulation. Distribution analysis indicated that ATIQCTPC accumulated and released ATIQC in the tumor tissue through a targeting manner. Thus, the antitumor and the anti-thrombotic activities of ATIQCTPC were 100-fold higher than those of ATIQC, and ATIQCTPC was able to prevent cancer patients from suffering from thrombosis. Based on the observation that ATIQCTPC decreased serum tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) in S180 mice, we hypothesized that this is the mechanism that ATIQCTPC utilized to slow tumor growth. Additionally, we observed that ATIQCTPC inhibited thrombosis by decreasing serum P-selectin of thrombotic rats. The intermolecular association and the hexamerization manner of ATIQCTPC were experimentally evidenced and correlated with the formation of the nanoparticles.

N-(3-hydroxymethyl-ß-carboline-1-yl-ethyl- 2-yl)-l-Phe: development toward a nanoscaled antitumor drug capable of treating complicated thrombosis and inflammation.

It is well documented that the surfaces of cancer cells, activated platelets and inflammatory cells are rich in P-selectin. N-(3-hydroxymethyl-ß-carboline-1-yl-ethyl-2-yl)-l-Phe (HMCEF) is a P-selectin inhibitor capable of simultaneously inhibiting thrombosis and inflammation. Based on the knowledge that P-selectin is a common target for antithrombotic, anti-inflammatory and antitumor drugs, the aim of this study article was to estimate the possibility of HMCEF as a nanoscaled antitumor drug. Images of transmission electron micro scopy, scanning electron microscopy and atomic force microscopy proved that HMCEF forms nanoparticles with a diameter of <120 nm that promote delivery in blood circulation. In vitro HMCEF intercalates into calf thymus DNA, cuts off DNA pBR22 and inhibits the proliferation of cancer cells. In vivo HMCEF dose dependently (0.2, 2 and 200 nmol/kg per day) slows tumor growth in treated S180 mice, and has a minimal effective dose of 2 nmol/kg per day. At 200 nmol/kg per day, HMCEF does not affect the liver and the kidney of the treated S180 mice, and at 20,000 nmol/kg HMCEF does not affect the liver and the kidney of the treated healthy ICR mice. HMCEF is a promising antitumor drug, which is characterized by its high safety and efficacy in the prevention of the complications of thrombosis and inflammation in patients.

Cholyl-l-lysine-carboxylbutyryl adriamycin prodrugs targeting chemically induced liver injury.

By use of carboxylbutyryl as a linker, adriamycin (ADR) and cholyl-l-Lys (an anti-inflammatory agent) were covalently conjugated and Nα-cholyl-Nε-(N-carbonylpropionoadriamycin)-l-Lys (BCBALys) was constructed as a liver-targeting nano-delivery system to release cholyl-l-Lys and protect the liver from CCl4-induced injury. In ultrapure water and rat plasma, 10-6 M BCBALys formed nanoparticles of 42-231 nm in diameter and ∼116 nm in height. In a CCl4-injured mouse model, however, only 2 µmol kg-1 of BCBALys effectively protected the liver of the mice from injury, and the mouse liver histology showed no hepatic architecture loss and inflammatory cell infiltration. BCBALys selectively accumulated in the liver of CCl4-injured mice, but not in other vital organs, and released cholyl-l-Lys. These data demonstrated that BCBALys exhibited high efficacy for treating CCl4-induced liver injury in a targeted manner. The chemical mechanism of BCBALys nanoparticle formation and the pharmacological mechanism of BCBALys mouse liver protection from CCl4-induced injury were also revealed by experiments.