Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis

被引:36
作者
Gabriel, Doris [1 ,4 ,5 ]
Lange, Norbert [1 ]
Chobaz-Peclat, Veronique [2 ,3 ]
Zuluaga, Maria Fernanda [1 ]
Gurny, Robert [1 ]
van den Bergh, Hubert [4 ,5 ]
Busso, Nathalie [2 ,3 ]
机构
[1] Univ Geneva, Univ Lausanne, Sect Pharmaceut Sci, Lab Pharmaceut & Biopharmaceut, CH-1211 Geneva, Switzerland
[2] CHU Vaudois, DAL, Serv Rheumatol, CH-1011 Lausanne, Switzerland
[3] Univ Lausanne, CH-1011 Lausanne, Switzerland
[4] Swiss Fed Inst Technol EPFL, Lab Photomed, Lausanne, Switzerland
[5] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland
基金
瑞士国家科学基金会;
关键词
Protease-sensitive prodrugs; Photodynamic therapy; Rheumatoid arthritis; Thrombin; Mice; COLLAGEN-INDUCED ARTHRITIS; PHOTODYNAMIC THERAPY; CONTRAST AGENT; TISSUE FACTOR; EXPRESSION; DISEASE; MODEL; FIBRINOLYSIS; SYNOVECTOMY; COAGULATION;
D O I
10.1016/j.jconrel.2012.08.022
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, towhichmultiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after irradiation. (c) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:178 / 186
页数:9
相关论文
共 41 条
[1]   Self-quenching polysaccharide-based nanogels of pullulan/folate-photosensitizer conjugates for photodynamic therapy [J].
Bae, Byoung-chan ;
Na, Kun .
BIOMATERIALS, 2010, 31 (24) :6325-6335
[2]   Synovial ablation in a rabbit rheumatoid arthritis model using photodynamic therapy [J].
Beischer, AD ;
Bhathal, P ;
de Steiger, R ;
Penn, D ;
Stylli, S .
ANZ JOURNAL OF SURGERY, 2002, 72 (07) :517-522
[3]   A NEW MACROMOLECULE AS A CONTRAST AGENT FOR MR-ANGIOGRAPHY - PREPARATION, PROPERTIES, AND ANIMAL STUDIES [J].
BOGDANOV, AA ;
WEISSLEDER, R ;
FRANK, HW ;
BOGDANOVA, AV ;
NOSSIF, N ;
SCHAFFER, BK ;
TSAI, E ;
PAPISOV, MI ;
BRADY, TJ .
RADIOLOGY, 1993, 187 (03) :701-706
[4]   Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD [J].
Busso, Nathalie ;
Karababa, Mahir ;
Nobile, Massimo ;
Rolaz, Aline ;
Van Gool, Frederic ;
Galli, Mara ;
Leo, Oberdan ;
So, Alexander ;
De Smedt, Thibaut .
PLOS ONE, 2008, 3 (05)
[5]   Novel Insights for Systemic Inflammation in Sepsis and Hemorrhage [J].
Cai, Bolin ;
Deitch, Edwin A. ;
Ulloa, Luis .
MEDIATORS OF INFLAMMATION, 2010, 2010
[6]   A tumor mRNA-triggered photodynamic molecular beacon based on oligonucleotide hairpin control of singlet oxygen production [J].
Chen, Juan ;
Lovell, Jonathan F. ;
Lo, Pui-Chi ;
Stefflova, Klara ;
Niedre, Mark ;
Wilson, Brian C. ;
Zheng, Gang .
PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES, 2008, 7 (07) :775-781
[7]   Selective antitumor effect of novel protease-mediated photodynamic agent [J].
Choi, Yongdoo ;
Weissleder, Ralph ;
Tung, Ching-Hsuan .
CANCER RESEARCH, 2006, 66 (14) :7225-7229
[8]   Photodynamic therapy for cancer [J].
Dolmans, DEJGJ ;
Fukumura, D ;
Jain, RK .
NATURE REVIEWS CANCER, 2003, 3 (05) :380-387
[9]   POLYMER CONJUGATES - PHARMACOKINETIC CONSIDERATIONS FOR DESIGN AND DEVELOPMENT [J].
DUNCAN, R ;
SPREAFICO, F .
CLINICAL PHARMACOKINETICS, 1994, 27 (04) :290-306
[10]   COLLAGEN-INDUCED ARTHRITIS AS A MODEL OF RHEUMATOID-ARTHRITIS [J].
DURIE, FH ;
FAVA, RA ;
NOELLE, RJ .
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY, 1994, 73 (01) :11-18