Discovery of water-soluble semicarbazide-containing sulfonamide derivatives possessing favorable anti-glaucoma effect in vivo and drug-like properties.

In order to obtain topical and non-irritating anti-glaucoma drugs, novel semicarbazide-containing sulfonamide derivatives were designed and synthetized by sugar tail method in this study. The hydrophilic monosaccharides were expected to form interaction with the hydrophilic site of hCA II meanwhile the linker semicarbazides are used to further enhance water solubility, and more importantly, regulate the pH values of the target compounds in aqueous solution. First, all target compounds were synthesized and evaluated for their CA inhibitory activities. The results showed our target compounds demonstrated comparable activity to the positive control drug acetazolamide. The best derivative 11d exhibits an IC50 value of 14 nM for hCA II and 2086-fold selectivity over CA I. Subsequently, physicochemical properties study showed that the target compounds displayed very good water solubility (up to 3 %) and neutral pH value in solutions. Meanwhile, the artificial membrane permeability assay was performed to verify that the target compound could also pass through the membrane structure despite their strong water solubility. In the glaucomatous rabbit eye model, the applied topically representative compounds showed strongly lowered intraocular pressure (IOP), as 1 % or 2 % water solutions. Subsequent drug-like evaluation showed our target compounds possessed low hemolysis effect and low cytotoxicity toward human corneal epithelial cell line. Also, it was not found that these target compounds had significant inhibition of hERG and CYP. In addition, these novel analogs also displayed good liver microsomal metabolic stability and plasma stability. Finally, docking studies provided the rational binding modes of representative compounds in complex with hCA II. Taken together, these results suggested that compound 11d may be a promising hCA II inhibitor deserving further development.

Investigation on Single-walled Carbon Nanotubes-Liposomes Conjugate to Treatment Tumor with Dual-mechanism.

Single-walled carbon nanotubes (SWNT) have been widely explored as carriers for drug delivery because of their large surface area, high near-infrared absorption coefficient and facile transport through cellular membranes. In this study, Lysine (Lys) modified SWNT-liposomes conjugate loaded with doxorubicin (DOX) was designed to enhance the targeted drug delivery and antitumor effect. The conjugate (DOX-Lys/SWNT-Lip) was prepared with pH gradient methods, and the mean particle size and drug entrapment efficiency were 223±5.9 nm and 85.9 %, respectively. In vitro drug release study showed that DOX released much slowly from DOX-Lys/SWNT-Lip than from DOX solution, but faster than that of DOX-Lys/SWNT. DOX-Lys/SWNT-Lip could efficiently cross the cell membrane and afford higher anti-tumor efficacy on MCF-7 cells in vitro. For in vivo experiment, normal saline (N.S.), and DOX or DOX-Lys/SWNTLip were given to the S180 tumor bearing mice by i.v. administration, and followed by exposing the tumor site to nearinfrared laser (NIR) irradiation at 808 nm for 2 min. The relative tumor volumes in DOX-Lys/SWNT-Lip group and DOX group were obviously smaller than those of N.S. group. When combined with NIR laser irradiation, the suppression on tumor growth was much stronger. In conclusion, this study may provide potentially viable clinical strategies for tumor treatment with chemotherapy and photothermal therapy dual-mechanism.

Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs.

In vitro and in vivo anti-cancer effects of targeting and photothermal sensitive solid lipid nanoparticles.

This report focuses on the in vitro and in vivo anti-cancer effects evaluation of targeting and photothermal sensitive solid lipid nanoparticles (SLN) for the co-loading of docetaxel (DTX), oxidized single-walled carbon nanotubes (OSWNT) and folic acid (FA). Compared with free DTX, FA-DTX-OSWNT-SLN could efficiently cross cell membranes and afford higher antitumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) in vitro. Annexin V-FITC/PI double staining further confirmed that FA-DTX-OSWNT-SLN induced higher apoptotic rates on SMMC-7721 cells. Meanwhile, the combination of near-infrared (NIR) laser irradiation at 808 nm with FA-DTX-OSWNT-SLN significantly enhanced cell inhibition. For in vivo experiments, the relative tumor volume of the sarcomaia 180 (S180) tumor-bearing mice in FA-DTX-OSWNT-SLN group was significantly smaller than that of control groups. Furthermore, when combining with NIR laser irradiation, the suppression on tumor growth was much stronger. In a word, FA-DTX-OSWNT-SLN in combination with 808 nm NIR laser could exhibit both in vitro and in vivo anti-tumor effects and may be a promising approach for cancer therapy.