Intelligent, Flexible Artificial Throats with Sound Emitting, Detecting, and Recognizing Abilities.

In recent years, there has been a notable rise in the number of patients afflicted with laryngeal diseases, including cancer, trauma, and other ailments leading to voice loss. Currently, the market is witnessing a pressing demand for medical and healthcare products designed to assist individuals with voice defects, prompting the invention of the artificial throat (AT). This user-friendly device eliminates the need for complex procedures like phonation reconstruction surgery. Therefore, in this review, we will initially give a careful introduction to the intelligent AT, which can act not only as a sound sensor but also as a thin-film sound emitter. Then, the sensing principle to detect sound will be discussed carefully, including capacitive, piezoelectric, electromagnetic, and piezoresistive components employed in the realm of sound sensing. Following this, the development of thermoacoustic theory and different materials made of sound emitters will also be analyzed. After that, various algorithms utilized by the intelligent AT for speech pattern recognition will be reviewed, including some classical algorithms and neural network algorithms. Finally, the outlook, challenge, and conclusion of the intelligent AT will be stated. The intelligent AT presents clear advantages for patients with voice impairments, demonstrating significant social values.

Synthesis of chitin nanocrystals supported Zn2+ with high activity against tobacco mosaic virus.

Chitin is a kind of natural nitrogenous organic polysaccharide. It contains antibacterial and antiviral properties, and it can induce plant disease resistance and promote plant growth. However, its application is constrained due to its insolubility and intricate molecular structure. Tobacco mosaic disease is caused by tobacco mosaic virus (TMV) infection, which seriously harms tobacco production. Zinc-containing chemical agents are commonly used to control tobacco mosaic disease, but overuse of chemical agents will cause serious environmental pollution. In this study, a novel nanomaterial (ChNC@Zn) was prepared by using chitin nanocrystals loaded with Zn2+, which has the function of inducing disease resistance to plants and reducing virus activity. When the Zn2+ concentration of ChNC@Zn is 105.6 µg/mL, it shows higher resistance to TMV than Lentinan (LNT). ChNC@Zn can improve the enzymes activities of peroxidase (POD) and catalase (CAT) in tobacco, and reduce the damage of reactive oxygen species (ROS) caused by TMV infection, thereby inducing resistance to TMV in tobacco. Besides, it can promote the growth of tobacco. As a result, ChNC@Zn can exhibit strong antiviral activity at low Zn2+ concentration and minimize the pollution of Zn2+ to the environment, which has high potential application value in the control of virus disease.

(1R,3S)-THCCA-Asn: To show the discovery of selective inhibitor of thrombin by successfully combining virtual screening and biological assay.

Thrombin is the most potent platelet aggregator. To discover the selective inhibitor of thrombin that is important to curing platelet aggregation-related diseases, docking experiments were performed to dock (1R,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1R,3S)-THCCA], and (1S,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1S,3S)-THCCA], into the p pocket of bovine thrombin. The ideal match supported that (1R,3S)-THCCA could be used as a potential lead compound. In this case 20 natural amino acids were theoretically introduced into the 3-carboxyl of (1R,3S)-THCCA and 20 derivatives, (1R,3S)-THCCA-amino acids, were docked into p pocket of bovine thrombin to perform virtual screening. The screening revealed that comparing to (1R,3S)-THCCA itself the DockScores of 16 derivatives were higher, and (1R,3S)-THCCA-Asn (4j) got the highest DockScore. Thus, 16 derivatives were synthesized for experimental study. The in vitro anti-platelet aggregation assay showed that at 100 µM of concentration the 16 derivatives failed to inhibit the platelet aggregation induced by both adenosine diphosphate and arachidonic acid. On the other hand, however, the IC50 value of the 16 derivatives inhibiting the platelet aggregation induced by platelet activating factor and thrombin ranged from 9.44 µM to 194.64 µM and from 0.07 µM to 9.56 µM, respectively. The in vitro anti-platelet aggregation assay suggested that the 16 derivatives selectively inhibited the platelet aggregation induced by thrombin. In particular, the IC50 of (1R,3S)-THCCA-Asn (4j) had the lowest value. On rat model at 1 nmol/kg of dosage the 16 derivatives effectively prevented thrombus formation. It is worth pointing out that even at 0.01 nmol/kg of dosage, 4j still effectively prevented thrombus formation. 4j hardly has effects on the proliferation of mammalian cells and rat tail bleeding time. In conclusion, the combination of virtual screening and biological assays successfully lead to the discovery of 4j as a promising candidate of selective inhibitor of thrombin.

Exploring the action of RGDV-gemcitabine on tumor metastasis, tumor growth and possible action pathway.

The coupling of Arg-Gly-Asp-Val (RGDV) and gemcitabine led to a hypothesis that the conjugate (RGDV-gemcitabine) could inhibit tumor metastasis. To confirm this hypothesis the activities of RGDV-gemcitabine inhibiting tumor metastasis in vitro and in vivo were presented for the first time. AFM (atomic force microscopy) imaged that RGDV-gemcitabine was able to adhere onto the surface of serum-starved A549 cells, to block the extending of the pseudopodia. Thereby RGDV-gemcitabine was able to inhibit the invasion, migration and adhesion of serum-starved A549 cells in vitro. On C57BL/6 mouse model RGDV-gemcitabine dose dependently inhibited the metastasis of planted tumor towards the lung and the minimal dose was 0.084 µmol/kg/3 days. The decrease of serum TNF-α (tumor necrosis factor), IL-8 (interleukin-8), MMP-2 (matrix metalloprotein-2) and MMP-9 (matrix metalloprotein-9) of the treated C57BL/6 mice was correlated with the action pathway of RGDV-gemcitabine inhibiting the metastasis of the planted tumor towards lung.

Development of 13-Cys-BBR as an Agent Having Dual Action of Anti-Thrombosis and Anti-Inflammation.

BACKGROUND: There is a correlation between tumor and inflammation. The activity of 13-[CH2CO-Cys(Bzl)-OBzl]-berberine (13-Cys-BBR) slowing tumor growth is higher than that of BBR. Whether the anti-inflammation activity of 13-Cys-BBR is higher than that of BBR remains unknown. There is a correlation between thrombosis and inflammation. Whether 13-Cys-BBR is an inhibitor of thrombosis remains unknown. PURPOSE: The object of this investigation is to compare the activities of 13-Cys-BBR inhibiting thrombosis and inflammation to those of BBR. METHODS: In vivo anti-thrombosis assay was performed on rat model of arterial and venous thrombosis. In vivo anti-inflammation assay was performed on mouse model of xylene induced ear edema. RESULTS: At oral dose of 66.7 nmol/kg, 13-Cys-BBR, but not BBR, inhibited the rats to form both venous thrombus and arterial thrombus. At oral dose of 2 µmol/kg, 13-Cys-BBR, but not BBR, inhibited the ears of the mice to occur edema. CONCLUSION: The anti-venous thrombosis activity, anti-arterial thrombosis activity and anti-inflammation activity of 13-Cys-BBR were significantly higher than those of BBR. 13-Cys-BBR is a promising preclinical candidate.

Modifying ICCA with Trp-Phe-Phe to Enhance in vivo Activity and Form Nano-Medicine.

BACKGROUND: 1-(4-isopropylphenyl)-ß-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-ß-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). PURPOSE: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. METHODS: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. RESULTS: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. CONCLUSION: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.

13-[CH2CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein.

BACKGROUND: The discovery of novel derivative of berberine (BBR) having higher anti-tumor activity in vivo is of clinical importance. In this profile, 13-[CH2CO-Cys-(Bzl)-OBzl]-berberine (13-Cys-BBR) was prepared for related assays. PURPOSE: The object of preparation and evaluation is to show the advantages of 13-Cys-BBR over BBR in both in vitro and in vivo anti-tumor actions, furthermore to correlate the proliferation of cancer cells with ROS formation and anti-apoptosis protein (XIAP) expression inside cancer cells. METHODS: Transwell chamber was used to simulate the intestinal and cell wall for bioavailability evaluation; MTT assay was used to evaluate the in vitro anti-proliferation activity; fluorescein isothiocyanate content was used to represent ROS level in HCT-8 cells; Western blot assay was used to quantify the expression of XIAP, caspase-3, and poly ADP-ribose polymerase in HCT-8 cells; and S180 mouse model was used to evaluate the in vivo anti-tumor activity. RESULTS: In vitro the IC50 values (~15-40 µM) of 13-Cys-BBR against the proliferation of eight cancer cell lines were significantly lower than those of BBR (~25-140 µM); the content of ROS formed inside HCT-8 cells treated by 13-Cys-BBR was ~3.44-folds higher than that inside HCT-8 cells treated by BBR; the expression of XIAP in HCT-8 cells treated by 13-Cys-BBR was ~1.21-folds lower than that in HCT-8 cells treated by BBR; the tumor weight of S180 mice orally treated by 2 µmol/kg/day of 13-Cys-BBR (~1.5 g) was significantly lower than that of S180 mice orally treated by 2 µmol/kg/day of BBR (~2.5 g); and the active pocket of XIAP was more suitable for 13-Cys-BBR than for BBR. CONCLUSION: The anti-tumor action correlates with ROS and apoptosis protein, which suggests 13-Cys-BBR is a promising candidate for preclinical study.

RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine.

BACKGROUND: Gemcitabine has been widely used as a chemotherapeutic drug. However, drug resistance, short half-life and side effects seriously decrease its chemotherapeutic efficacy. PURPOSE: The object of preparing RGDV-gemcitabine was to prolong the half-life, to overcome drug resistance and to eliminate bone marrow toxicity of gemcitabine. METHODS: Arg-Gly-Asp-Val was coupled with gemcitabine, forming 4-(Arg-Gly-Asp-Val-amino)-1-[3,3-difluoro-4-hydroxy-5-(hydroxylmethyl)oxo-lan-2-yl]pyrimidin-2-one (RGDV-gemcitabine) involving 9-step reactions. The advantages of RGDV-gemcitabine to gemcitabine were demonstrated by a series of assays, such as in vitro half-life assay, in vitro drug resistance assay, in vivo anti-tumor assay, in vivo kidney toxicity assay, in vivo liver toxicity assay and in vivo marrow toxicity assay. The nano-features of RGDV-gemcitabine were visualized by TEM, SEM and AFM images. The tumor-targeting action and release of RGDV-gemcitabine were evidenced by FT-MS spectra. RESULTS: Half-life and anti-tumor activity of RGDV-gemcitabine were 17-fold longer and 10-fold higher than that of gemcitabine, respectively. RGDV-gemcitabine, but not gemcitabine, showed no kidney toxicity, no liver toxicity, no marrow toxicity and no drug resistance. The advantages attributed to the nanofeatures of RGDV-gemcitabine were targeting tumor tissue and releasing gemcitabine in tumor tissue. CONCLUSION: RGDV-gemcitabine successively overcame the defects of gemcitabine and provided a practical strategy of nano-medicine.

Nano-scaled MTCA-KKV: for targeting thrombus, releasing pharmacophores, inhibiting thrombosis and dissolving blood clots in vivo.

BACKGROUND: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. METHODS: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. RESULTS: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. CONCLUSION: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.

BCESA: a nano-scaled intercalator capable of targeting tumor tissue and releasing anti-tumoral ß-carboline-3-carboxylic acid.

Background: In the discovery of DNA intercalators, ß-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-ß-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity. Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models. Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 µmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice. Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral ß-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.

Dimethyl 2,2'-[2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]-diacetate: a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect.

BACKGROUND: Due to the discovery that deep venous thrombosis (DVT) inhibitor is of chemotherapeutic importance, the nano-property of dimethyl 2,2'-[2,2'-(ethane-1,1-diyl) bis(1H-indole-3,2-diyl)]-diacetate (DEBIC), a recently reported antitumor agent, is worthy of characterization. MATERIALS AND METHODS: One-pot reaction was used to prepare DEBIC. Electrospray Ionization (+/-)-Fourier Transform-Ion Cyclotron Resonance-Mass Spectrometer (ESI(+/-)-FT-ICR-MS), quadrupole Collision Induced Dissociation (qCID) and nuclear overhauser effect spectroscopy spectra were used to present the assembly of DEBIC. Transmission electron microscopy, scanning electron microscopy, atomic force microscopy and Faraday-Tyndall effect were used to visualize the nano-property of DEBIC. Rat models were used to evaluate DVT inhibition and the bleeding reaction of DEBIC. RESULTS: One-pot reaction can provide DEBIC in acceptable yield and high purity. In water, rat plasma and lyophilized powders of DEBIC existed as particles of small nano-size. In vivo DEBIC inhibited DVT in a dose-dependent manner. The minimal effective dose of DEBIC was 1.7 µmol/kg. Even the dose of 36 µmol/kg/day DEBIC did not induce bleeding side effect in DVT rats like in warfarin (0.82 µmol/kg/day). CONCLUSION: DEBIC is a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect.

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 development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors.

BACKGROUND: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. METHODS: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-ß-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors. RESULTS: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 µmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. CONCLUSION: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.

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.

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.

Loading cisplatin onto 6-mercaptopurine covalently modified MSNS: a nanomedicine strategy to improve the outcome of cisplatin therapy.

In the treatment of cancer patients, cisplatin (CDDP) exhibits serious cardiac and renal toxicities, while classical combinations related to CDDP are unable to solve these problems and may result in worse prognosis. Alternately, this study covalently conjugated 6-mercaptopurine (6MP) onto the surface of mercapto-modified mesoporous silica nanoparticles (MSNS) to form MSNS-6MP and loaded CDDP into the holes on the surface of MSNS-6MP to form MSNS-6MP/CDDP, a tumor-targeting nano-releasing regime for CDDP and 6MP specifically. In the S180 mouse model, the anti-tumor activity and overall survival of MSNS-6MP/CDDP (50 mg·kg-1·day-1, corresponding to 1 mg·kg-1·day-1 of 6MP and 5 mg·kg-1·day-1 of CDDP) were significantly higher than those of CDDP alone (5 mg·kg-1·day-1) or CDDP (5 mg·kg-1·day-1) plus 6MP (1 mg·kg-1·day-1). The assays of serum alanine aminotransferase, aspartate aminotransferase and creatinine, as well as the images of myocardium and kidney histology, support that MSNS-6MP/CDDP is able to completely eliminate liver, kidney and heart toxicities induced by CDDP alone or CDDP plus 6MP.