根据美国国家科学院院刊 (Proceedings of the National Academy of Sciences)最新一期的一份报告指出,由美国耶鲁大学 (Yale University)与罗得岛大学 (University of Rhode Island) 共同发展出来的一项新的技术,可以利用小片段的蛋白质,像奈米针筒一样将标示(tags) 黏附到肿瘤细胞上,临床上不但可以藉此标示分裂失序的肿瘤细胞,未来还有可能因此发展出更有效的肿瘤治疗方法。
参与这次研究计划的科学家表示,这种称为 pHLIP(pH (Low) Insertion Peptide)的蛋白质片段,可以用注射的方式,进入罹患乳癌肿瘤细胞的小鼠腹部,大约经过 20个小时的时间, pHLIP分子会经由血管的输送,累积于乳癌肿瘤细胞内。
就目前的实验数据看来,此分子的专一性非常的高,因此再小的肿瘤组织,都会被发现并且屯积 pHLIP分子,研究人员可以利用荧光探针的方法,标示 pHLIP分子,透过追踪荧光的位置,就等于发现癌细胞的落脚处,此外利用 pHLIP分子,携带有效的抗癌药物,那么就算是再隐蔽的癌细胞,都躲不过 pHLIP分子的追杀。
参与的科学家表示, pHLIP分子的活动,原则上是以组织变酸的变化,作为筛选的工具,因此应该不仅仅只有酸化的癌细胞可用,将来连组织因为发炎,而导致酸化的关结炎、局部缺血与中风,都有可能因此找到新的治疗方法。
(许仁旗译) (资料来源 : Bio.com)
英文原文链接:
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?cid=28900004
原始出处:
Published online before print May 1, 2007, 10.1073/pnas.0702439104
PNAS | May 8, 2007 | vol. 104 | no. 19 | 7893-7898
Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues in vivo
Oleg A. Andreev*,, Allison D. Dupuy, Michael Segala*, Srikanth Sandugu*, David A. Serra, Clinton O. Chichester, Donald M. Engelman,¶, and Yana K. Reshetnyak*,,¶
*Physics Department, University of Rhode Island, 2 Lippitt Road, Kingston, RI 02881; Department of Molecular Biophysics and Biochemistry, Yale University, P.O. Box 208114, New Haven, CT 06520; Research Office, University of Rhode Island, 70 Lower College Road, Kingston, RI 02881; and Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Fogarty Hall, 41 Lower College Road, Kingston, RI 02881
Contributed by Donald M. Engelman, March 17, 2007 (received for review December 19, 2006)
Abstract
The pH-selective insertion and folding of a membrane peptide, pHLIP [pH (low) insertion peptide], can be used to target acidic tissue in vivo, including acidic foci in tumors, kidneys, and inflammatory sites. In a mouse breast adenocarcinoma model, fluorescently labeled pHLIP finds solid acidic tumors with high accuracy and accumulates in them even at a very early stage of tumor development. The fluorescence signal is stable for >4 days and is approximately five times higher in tumors than in healthy counterpart tissue. In a rat antigen-induced arthritis model, pHLIP preferentially accumulates in inflammatory foci. pHLIP also maps the renal cortical interstitium; however, kidney accumulation can be reduced significantly by providing mice with bicarbonate-containing drinking water. The peptide has three states: soluble in water, bound to the surface of a membrane, and inserted across the membrane as an -helix. At physiological pH, the equilibrium is toward water, which explains its low affinity for cells in healthy tissue; at acidic pH, titration of Asp residues shifts the equilibrium toward membrane insertion and tissue accumulation. The replacement of two key Asp residues located in the transmembrane part of pHLIP by Lys or Asn led to the loss of pH-sensitive insertion into membranes of liposomes, red blood cells, and cancer cells in vivo, as well as to the loss of specific accumulation in tumors. pHLIP nanotechnology introduces a new method of detecting, targeting, and possibly treating acidic diseased tissue by using the selective insertion and folding of membrane peptides.
cancer targeting | imaging | peptide insertion
Fig. 1. Imaging tumors and inflammation. (a) The mechanism of pHLIP interaction with lipid bilayers. The peptide has three states: soluble in water, bound to the surface of a membrane (at normal pH 7.4), and inserted across the membrane as an -helix (at low pH). (b) Overlay of pHLIP-Cy5.5 fluorescence and light images of mice bearing a tumor (7 mm in diameter, 12 d after 106 cell implant) in the right flank obtained on the homemade imager (i.p. injection of 500 µg/kg of pHLIP-Cy5.5 1 d before imaging). (c) pHLIP-Alexa750 fluorescent image (excitation 750 nm, emission 800 nm, artificial green color) of mice bearing a tumor (2 mm in diameter 6 d after 106 cell implant) in the right flank obtained on the IR scanner with focal distance set at 3 mm, which allows for the collection of light from the interior of the body (i.p. injection of 300 µg/kg of pHLIP-Alexa750 1 d before imaging). Reflectance is denoted in red (excitation 680 nm). (d) pHLIP-Cy5.5 given as a single i.p. injection (200 µg/kg) into the left side of mice initially diffused into the left flank, but 20 h later it accumulated in a tumor on the right flank. The fluorescent image of the back part of each mouse is presented. Blue color represents the background fluorescent signal, and the red color represents a high intensity of the fluorescence signal. (e–h) Overlay of pHLIP-Cy5.5 (500 µg/kg) fluorescence and light images of back part of mice bearing tumors of different sizes in right flanks: (e) undetectable by eye at time of imaging 5 d after 105 cell implant, (f) 3 x 4 mm (8 d after 106 cell implant), (g) 5 x 6 mm (12 d after 106 cell implant), (h) 8 x 9 mm (18 d after 106 cell implant). (i) Accumulation of pHLIP- Cy5.5 (2 days after i.p injection, 30 µg/kg) in inflammation sites is shown by overlay of pHLIP fluorescence and photo images of rat right (arthritis) and left (control) legs. The arthritis was induced in the right leg by injection of methylated BSA and Freund's complete adjuvant (the left knee of the rat received a sham injection of saline and was used as a control). A substantial fluorescence signal (4–5 times higher than in the left knee joint) was detected in the right knee (1), especially in the knee joint (2) (red color represents high fluorescence intensity).
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