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[前沿] [生科综合] 纳米蜂毒肽的抗肿瘤作用

[前沿] [生科综合] 纳米蜂毒肽的抗肿瘤作用

前沿

原创与否 -
纳米蜂毒肽的抗肿瘤作用

ScienceDaily(2009年8月31日) -当被蜜蜂螫时,他们向受害者体内泵入蜂毒。华盛顿大学医学院的研究人员在圣路易斯的说:“现在,在蜂毒毒素已被利用杀死肿瘤细胞”。研究人员附上了蜂毒纳米大小的领域的主要组成部分,他们称之为nanobees。

在老鼠体内测试,nanobees将蜜蜂蜂毒素传递至肿瘤的同时保护了毒素的破坏其他组织,使肿瘤在小鼠体内停止生长或缩小。Nanobees的抗癌功效事先发表在8月10日在线公共临床研究杂志上。

共同作者Samuel Wickline博士(负责华盛顿大学癌症纳米技术的研究)说:“nanobees停留在细胞表面,使蜂毒肽迅速与靶细胞融合”, “我们已经表明,蜂毒素可以在它的内部结构上戳个洞然后进入细胞。”

蜂毒是一种小型蛋白质或缩氨酸,可以吸附到细胞膜上,在细胞上可以形成微孔导致细胞破裂,并杀死他们。

“蜂毒一直是研究者很感兴趣的对象,因为在足够高的浓度下它可以摧毁任何与之接触到的细胞,使之成为一项有效的抗菌和抗真菌剂和潜在的抗癌药,”共同作者细胞生物学和生理学副教授Paul Schlesinger博士说: “癌症细胞能对许多抗癌药物适应,产生耐药性,从而改变基因功能或目标细胞的DNA,但是很难找到一种机制用蜂毒来杀死细胞。”

改编自华盛顿大学医学院提供的材料。原始文章,格温埃里克松写的。
科学家在两种肿瘤小鼠体内测试了nanobees。一种老鼠被植入人乳腺癌细胞,其他的植入黑色素瘤。在注射了携带蜂毒肽的纳米粒子4至5天后,与未经处理的小鼠相比,种植了乳腺癌细胞的老鼠体内肿瘤生长减缓了近百分之二十五,黑色素瘤小鼠的肿瘤大小减少百分之88。

研究表明,这些实体肿瘤中收集的nanobees往往因为肿瘤血管渗漏,易于保留材料。科学家称这种现象为加强渗透性和肿瘤的保留效果,并解释了药物在肿瘤组织中集中远远超过正常组织的原因。

但是,研究人员还开发作出更具体的方法(nanobees与其他成分的偶联),确保nanobees对肿瘤的靶向。他们加入了一个可以吸附到肿瘤周围血管得靶目标,引导nanobees至血供丰富的癌前病变皮肤。小鼠体内注射nanobees减少了癌前皮肤的百分之八十的增殖程度。

总的来说,结果表明,nanobees不仅可以减慢已经形成了癌症肿瘤的增长速度,而且在肿瘤早期阶段采取行动,阻止癌症发展。

“Nanobees是一种有效的方法,但可能致命,我们将蜂毒肽与纳米结合将其封闭,使它不伤害正常细胞,也不会在它达到的目标前被降解,”施莱辛格说。

如果大量的蜂毒肽注射到血液中,直接会导致红细胞将被广泛破坏。研究表明,纳米粒子保护小鼠红细胞和其它组织免受蜂毒素的毒性作用。将 Nanobees注入血液中不伤害老鼠。他们的红细胞计数正常,器官损害的血源性酶为阴性。

"我们可以在纳米建立后将我们的蜂毒加入," Wickline 说. “如果我们已经开发纳米粒子做为载体,并给了他们一个靶点,我们可以再添加不同成份的蜂毒肽或者蜂毒肽样蛋白,而不需要重建载体。蜂毒进入纳米粒子的速度非常快和完全,并且在与细胞接触之前nanobee仍然有效。“

nanobees和其他纳米微粒具有灵活性,他们可以适应需要医疗的情况随时调整。赋予显像能力的纳米粒子可以对多少药物到达肿瘤以及肿瘤如何反映给与指示。

“这将为特定病人制定医疗方案成为可能”施莱辛格说。 “我们正在学习更多有关肿瘤生物学的知识,以便我们能够使用nanobee的办法更快的创建针对肿瘤的目标纳米粒子。”

来自美国国立卫生研究院和美国心脏协会的经费支持这项研究。

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期刊参考:

Soman NR, Baldwin SL, Hu G, Marsh JN, Lanza GM, Heuser JE, Arbeit JM, Wickline SA, Schlesinger PH.。分子靶向纳米载体提供小鼠的肿瘤细胞的靶向细胞毒性蜂毒肽,抑制肿瘤的生长。临床调查,2009年8月10日(网络版上公布)


Tumors Feel The Deadly Sting Of Nanobees

ScienceDaily (Aug. 31, 2009) — When bees sting, they pump poison into their victims. Now the toxin in bee venom has been harnessed to kill tumor cells by researchers at Washington University School of Medicine in St. Louis. The researchers attached the major component of bee venom to nano-sized spheres that they call nanobees.

In mice, nanobees delivered the bee toxin melittin to tumors while protecting other tissues from the toxin's destructive power. The mice's tumors stopped growing or shrank. The nanobees' effectiveness against cancer in the mice is reported in advance online publication Aug. 10 in the Journal of Clinical Investigation.

"The nanobees fly in, land on the surface of cells and deposit their cargo of melittin which rapidly merges with the target cells," says co-author Samuel Wickline, M.D., who heads the Siteman Center of Cancer Nanotechnology Excellence at Washington University. "We've shown that the bee toxin gets taken into the cells where it pokes holes in their internal structures."

Melittin is a small protein, or peptide, that is strongly attracted to cell membranes, where it can form pores that break up cells and kill them.

"Melittin has been of interest to researchers because in high enough concentration it can destroy any cell it comes into contact with, making it an effective antibacterial and antifungal agent and potentially an anticancer agent," says co-author Paul Schlesinger, M.D., Ph.D., associate professor of cell biology and physiology. "Cancer cells can adapt and develop resistance to many anticancer agents that alter gene function or target a cell's DNA, but it's hard for cells to find a way around the mechanism that melittin uses to kill."

The scientists tested nanobees in two kinds of mice with cancerous tumors. One mouse breed was implanted with human breast cancer cells and the other with melanoma tumors. After four to five injections of the melittin-carrying nanoparticles over several days, growth of the mice's breast cancer tumors slowed by nearly 25 percent, and the size of the mice's melanoma tumors decreased by 88 percent compared to untreated tumors.

The researchers indicate that the nanobees gathered in these solid tumors because tumors often have leaky blood vessels and tend to retain material. Scientists call this the enhanced permeability and retention effect of tumors, and it explains how certain drugs concentrate in tumor tissue much more than they do in normal tissues.

But the researchers also developed a more specific method for making sure nanobees go to tumors and not healthy tissue by loading the nanobees with additional components. When they added a targeting agent that was attracted to growing blood vessels around tumors, the nanobees were guided to precancerous skin lesions that were rapidly increasing their blood supply. Injections of targeted nanobees reduced the extent of proliferation of precancerous skin cells in the mice by 80 percent.

Overall, the results suggest that nanobees could not only lessen the growth and size of established cancerous tumors but also act at early stages to prevent cancer from developing.

"Nanobees are an effective way to package the useful, but potentially deadly, melittin, sequestering it so that it neither harms normal cells nor gets degraded before it reaches its target," Schlesinger says.

If a significant amount of melittin were injected directly into the bloodstream, widespread destruction of red blood cells would result. The researchers showed that nanoparticles protected the mice's red cells and other tissues from the toxic effects of melittin. Nanobees injected into the bloodstream did not harm the mice. They had normal blood counts, and tests for the presence of blood-borne enzymes indicative of organ damage were negative.

When secured to the nanobees, melittin is safe from protein-destroying enzymes that the body produces. Although unattached melittin was cleared from the mice's circulation within minutes, half of the melittin on nanobees was still circulating 200 minutes later. Schlesinger indicates that is long enough for the nanobees to circulate through the mice's bloodstream 200 times, giving them ample time to locate tumors.

"Melittin is a workhorse," says Wickline, also professor of medicine in the Cardiovascular Division and professor of physics, of biomedical engineering and of cell biology and physiology. "It's very stable on the nanoparticles, and it's easily and cheaply produced. We are now using a nontoxic part of the melittin molecule to hook other drugs, targeting agents or imaging compounds onto nanoparticles."

The core of the nanobees is composed of perfluorocarbon, an inert compound used in artificial blood. The research group developed perfluorocarbon nanoparticles several years ago and have been studying their use in various medical applications, including diagnosis and treatment of atherosclerosis and cancer. About six millionths of an inch in diameter, the nanoparticles are large enough to carry thousands of active compounds, yet small enough to pass readily through the bloodstream and to attach to cell membranes.

"We can add melittin to our nanoparticles after they are built," Wickline says. "If we've already developed nanoparticles as carriers and given them a targeting agent, we can then add a variety of components using native melittin or melittin-like proteins without needing to rebuild the carrier. Melittin fortunately goes onto the nanoparticles very quickly and completely and remains on the nanobee until cell contact is made."

The flexibility of nanobees and other nanoparticles made by the group suggests they could be readily adapted to fit medical situations as needed. The ability to attach imaging agents to nanoparticles means that the nanoparticles can give a visible indication of how much medication gets to tumors and how tumors respond.

"Potentially, these could be formulated for a particular patient," Schlesinger says. "We are learning more and more about tumor biology, and that knowledge could soon allow us to create nanoparticles targeted for specific tumors using the nanobee approach."

Funding from the National Institutes of Health and the American Heart Association supported this research.

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Journal reference:

Soman NR, Baldwin SL, Hu G, Marsh JN, Lanza GM, Heuser JE, Arbeit JM, Wickline SA, Schlesinger PH. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. Journal of Clinical Investigation, August 10, 2009 (advance online publication)
Adapted from materials provided by Washington University School of Medicine. Original article written by Gwen Ericson.

http://www.sciencedaily.com/releases/2009/08/090810174226.htm


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