根據(jù)美國國家科學院院刊 (Proceedings of the National Academy of Sciences)最新一期的一份報告指出,，由美國耶魯大學 (Yale University)與羅得島大學 (University of Rhode Island) 共同發(fā)展出來的一項新的技術,，可以利用小片段的蛋白質(zhì),，像奈米針筒一樣將標示(tags) 黏附到腫瘤細胞上，臨床上不但可以藉此標示分裂失序的腫瘤細胞,，未來還有可能因此發(fā)展出更有效的腫瘤治療方法。
參與這次研究計劃的科學家表示,，這種稱為 pHLIP(pH (Low) Insertion Peptide)的蛋白質(zhì)片段，可以用注射的方式,，進入罹患乳癌腫瘤細胞的小鼠腹部，大約經(jīng)過 20個小時的時間,， pHLIP分子會經(jīng)由血管的輸送，累積于乳癌腫瘤細胞內(nèi),。
就目前的實驗數(shù)據(jù)看來，此分子的專一性非常的高,，因此再小的腫瘤組織，都會被發(fā)現(xiàn)并且屯積 pHLIP分子,，研究人員可以利用熒光探針的方法，標示 pHLIP分子,，透過追蹤熒光的位置,，就等于發(fā)現(xiàn)癌細胞的落腳處,，此外利用 pHLIP分子，攜帶有效的抗癌藥物,，那么就算是再隱蔽的癌細胞,，都躲不過 pHLIP分子的追殺。
參與的科學家表示,， pHLIP分子的活動，原則上是以組織變酸的變化,，作為篩選的工具，因此應該不僅僅只有酸化的癌細胞可用,，將來連組織因為發(fā)炎，而導致酸化的關結炎,、局部缺血與中風,，都有可能因此找到新的治療方法,。
（許仁旗譯） (資料來源 : Bio.com)
英文原文鏈接：
http://www.bio.com/newsfeatures/newsfeatures_research.jhtml?cid=28900004
原始出處:
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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