Dual 7-ethyl-10-hydroxycamptothecin conjugated phospholipid prodrug assembled liposomes with in vitro anticancer effects. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Du, Yawei; Zhang, Wei; He, Ruiyu; Ismail, Muhammad; Ling, Longbing; Yao, Chen; Fu, Zhenglin; Li, Xinsong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3247
• Page End: 3258
• Publication Date: 2017-06-15
• Subjects: SN38 7-ethyl-10-hydroxycamptothecin -- CPT-11 irinotecan -- TEM transmission electron microscopy -- cyro-TEM cryogenic transmission electron microscopy -- FDA Food and Drug Administration -- DDS drug delivery system -- EPR enhanced permeability and retention -- RES reticuloendothelial system -- Di-SN38-PC dual SN38 phospholipid conjugate -- GPC l-α-glycerophosphorylcholine -- MTT methyl thiazolyl tetrazolium -- CFA colony formation assay -- RT-PCR reverse transcription-polymerase chain reaction -- SN38-SA SN38-20-O-succinic acid -- CAC critical aggregation concentration -- Dh hydration diameter -- PDI particle dispersion index -- CLSM laser confocal scanning microscopy -- IC50 half-maximal inhibitory concentration -- Cmax maximum platinum concentration -- t1/2 half life time -- CL clearance -- AUC area under the curve -- MRT mean residence time -- VRT variance of residence time -- DMAP 4-dimethylaminopyridine -- CDI 1, 1′-carbonyldiimidazole -- DBU 1, 8-diaza-(5, 4, 0)-undec-7-ene -- DMEM Dulbecco's modified eagle medium -- FBS fetal bovine serum -- ACN acetonitrile -- DLS dynamic light scattering -- PI propidium iodide -- OD optical density -- HRP horseradish peroxidase -- ECL enhanced chemiluminescence -- AU arbitrary unit; 7-Ethyl-10-hydroxycamptothecin -- Prodrug -- Liposome -- Anticancer activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.025
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 7-Ethyl-10-hydroxycamptothecin (SN38), as a highly active topoisomerase I inhibitor, is 200–2000-fold more cytotoxic than irinotecan (CPT-11) commercially available as Camptosar®. However, poor solubility and low stability extensively restricted its clinical utility. In this report, dual SN38 phospholipid conjugate (Di-SN38-PC) prodrug based liposomes were developed in order to compact these drawbacks. Di-SN38-PC prodrug was first synthesized by inhomogeneous conjugation of two SN38-20- O -succinic acid molecules with L- α -glycerophosphorylcholine (GPC). The assembly of the prodrug was carried out without any excipient by using thin film method. Dynamic light scattering (DLS), transmission electron microscope (TEM) and cryogenic transmission electron microscopy (cyro-TEM) characterization indicated that Di-SN38-PC can form spherical liposomes with narrow particle size (<200 nm) and negatively charged surface (-21.6 ± 3.5 mV). The loading efficiency of SN38 is 65.2 wt.% after a simple calculation. In vitro release test was further performed in detail. The results demonstrated that Di-SN38-PC liposomes were stable in neutral environment but degraded in a weakly acidic condition thereby released parent drug SN38 effectively. Cellular uptake studies reflected that the liposomes could be internalized into cells more significantly than SN38. In vitro antitumor activities were finally evaluated by MTT assay, colony formation assay, flow cytometry, RT-PCR analysis and Western Blot. The results showed that Di-SN38-PC liposomes had a comparable cytotoxicity with SN38 against MCF-7 and HBL-100, and a selective promotion of apoptosis of tumor cells. Furthermore, a pharmacokinetics test showed that Di-SN38-PC liposomes had a longer circulating time in blood compared with the parent drug. All the results indicate that Di-SN38-PC liposomes are an effective delivery system of SN38.