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Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation.

ABSTRACT: Photodynamic therapy (PDT) uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6) with a human interleukin-6 receptor (IL-6R) binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R(+)) cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.Molecular Therapy-Nucleic Acids (2014) 3, e143; doi:10.1038/mtna.2013.70; published online 21 January 2014.

SUBMITTER: Kruspe S

PROVIDER: S-EPMC3910004 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation.

Kruspe Sven S Meyer Cindy C Hahn Ulrich U

Molecular therapy. Nucleic acids 20140121

Photodynamic therapy (PDT) uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6) with a human interleukin-6 r ...[more]

PMID: 24481022

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Project description:The main purpose of this study is to synthesize novel types of nanophotosensitizers that are based on hyperbranched chlorin e6 (Ce6) via disulfide linkages. Moreover, hyperbranched Ce6 was conjugated with hyaluronic acid (HA) for CD44-receptor mediated delivery and redox-sensitive photodynamic therapy (PDT) against cancer cells. Hyperbranched Ce6 was considered to make novel types of macromolecular photosensitizer since most of the previous studies regarding nanophotosensizers are concerned with simple conjugation between monomeric units of photosensitizer and polymer materials. Hyperbranched Ce6 was synthesized by conjugation of Ce6 each other while using disulfide linkage. To synthesize Ce6 tetramer, carboxyl groups of Ce6 were conjugated with cystamine and three equivalents of Ce6 were then conjugated again with the end of amine groups of Ce6-cystamine. To synthesize Ce6 decamer as a hyperbranched Ce6, six equivalents of Ce6 was conjugated with the end of Ce6 tetramer via cystamine linkage. Furthermore, HA-cystamine was attached with Ce6 tetramer or Ce6 decamer to synthesize HA-Ce6 tetramer (Ce6tetraHA) or HA-Ce6 decamer (Ce6decaHA) conjugates. Ce6tetraHA and Ce6decaHA nanophotosensitizers showed small diameters of less than 200 nm. The addition of dithiothreitol (DTT) and hyaluronidase (HAse) induced a faster Ce6 release rate in vitro drug release study, which indicated that Ce6tetraHA nanophotosensitizers possess redox-sensitive and HAse-sensitive release properties. Ce6tetraHA nanophotosensitizers showed higher intracellular Ce6 accumulation, higher ROS generation, and higher PDT efficacy than that of Ce6 alone. Ce6tetraHA nanophotosensitizers responded to the CD44 receptor of cancer cell surface, i.e., the pre-treatment of HA blocked CD44 receptor of U87MG or HCT116 cells and then inhibited delivery of nanophotosensitizers in vitro cell culture study. Furthermore, in vivo tumorxenograft study showed that fluorescence intensity in the tumor tissues was stronger than those of other organs, while CD44 receptor blocking by HA pretreatment induced a decrease of fluorescence intensity in tumor tissues when compared to liver. These results indicated that Ce6tetraHA nanophotosensitizers delivered to tumors by redox-sensitive and CD44-sensitive manner.

Project description:The aim of this study is to prepare redox-sensitive nanophotosensitizers for the targeted delivery of chlorin e6 (Ce6) against cervical cancer. For this purpose, Ce6 was conjugated with β-cyclodextrin (bCD) via a disulfide bond, creating nanophotosensitizers that were fabricated for the redox-sensitive delivery of Ce6 against cancer cells. bCD was treated with succinic anhydride to synthesize succinylated bCD (bCDsu). After that, cystamine was attached to the carboxylic end of bCDsu (bCDsu-ss), and the amine end group of bCDsu-ss was conjugated with Ce6 (bCDsu-ss-Ce6). The chemical composition of bCDsu-ss-Ce6 was confirmed with 1H and 13C NMR spectra. bCDsu-ss-Ce6 nanophotosensitizers were fabricated by a dialysis procedure. They formed small particles with an average particle size of 152.0 ± 23.2 nm. The Ce6 release rate from the bCDsu-ss-Ce6 nanophotosensitizers was accelerated by the addition of glutathione (GSH), indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive photosensitizer delivery capacity. The bCDsu-ss-Ce6 nanophotosensitizers have a low intrinsic cytotoxicity against CCD986Sk human skin fibroblast cells as well as Ce6 alone. However, the bCDsu-ss-Ce6 nanophotosensitizers showed an improved Ce6 uptake ratio, higher reactive oxygen species (ROS) production, and phototoxicity compared to those of Ce6 alone. GSH addition resulted in a higher Ce6 uptake ratio, ROS generation, and phototoxicity than Ce6 alone, indicating that the bCDsu-ss-Ce6 nanophotosensitizers have a redox-sensitive biological activity in vitro against HeLa human cervical cancer cells. In a tumor xenograft model using HeLa cells, the bCDsu-ss-Ce6 nanophotosensitizers efficiently accumulated in the tumor rather than in normal organs. In other words, the fluorescence intensity in tumor tissues was significantly higher than that of other organs, while Ce6 alone did not specifically target tumor tissue. These results indicated a higher anticancer activity of bCDsu-ss-Ce6 nanophotosensitizers, as demonstrated by their efficient inhibition of the growth of tumors in an in vivo animal tumor xenograft study.

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Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation.

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Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation.

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