Nanoparticle screen could speed up drug development

纳米颗粒筛选加速药物研发

Many scientists are pursuing ways to treat disease by delivering DNA or RNA that can turn a gene on or off. However, a major obstacle to progress in this field has been finding ways to safely deliver that genetic material to the correct cells.
很多科学工作者都在寻求通过传递可开启或关闭基因的DNA或RNA来治疗的方法。然而，在这一领域取得进展的一大障碍就是寻找安全传递遗传物质到正确细胞的方法。

Encapsulating strands of RNA or DNA in tiny particles is one promising approach. To help speed up the development of such drug-delivery vehicles, a team of researchers from MIT, Georgia Tech, and the University of Florida has now devised a way to rapidly test different nanoparticles to see where they go in the body.
包覆RNA或DNA是一个有前景的途径。为了加速这种药物运载工具的研发，来自 MIT, Georgia Tech, 和 the University of Florida的研究团队开发了一种快速测试不同纳米颗粒在体内的去处的方法。
"Drug delivery is a really substantial hurdle that needs to be overcome," says James Dahlman, a former MIT graduate student who is now an assistant professor at Georgia Tech and the study's lead author. "Regardless of their biological mechanisms of action, all genetic therapies need safe and specific drug delivery to the tissue you want to target."
“药物运载是需要攻克的难关，” James Dahlman，前MIT研究生、现Georgia Tech助理教授、文章的第一作者，说。“不管它们的生物作用机制如何，所有的基因疗法都需要安全、特定的将药物运载到靶组织的方式。”
This approach, described in the Proceedings of the National Academy of Sciences the week of Feb. 6, could help scientists target genetic therapies to precise locations in the body.
这一方式，发表在2月6号这周的 Proceedings of the National Academy of Sciences ，可以帮助科研工作者研发针对体内精确位置的基因疗法。
"It could be used to identify a nanoparticle that goes to a certain place, and with that information we could then develop the nanoparticle with a specific payload in mind," says Daniel Anderson, an associate professor in MIT's Department of Chemical Engineering and a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).
“它可以用于确认去确定位置的纳米颗粒，利用这些信息，我们接下来可以在理论上开发特定负载的纳米颗粒，”Daniel Anderson，MIT化工系助理教授、MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES)的一员。
The paper's senior authors are Anderson; Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute; and Eric Wang, a professor at the University of Florida. Other authors are graduate student Kevin Kauffman, recent MIT graduates Yiping Xing and Chloe Dlott, MIT undergraduate Taylor Shaw, and Koch Institute technical assistant Faryal Mir.
文章的主要作者有Anderson; Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute; and Eric Wang, a professor at the University of Florida. Other authors are graduate student Kevin Kauffman, recent MIT graduates Yiping Xing and Chloe Dlott, MIT undergraduate Taylor Shaw, and Koch Institute technical assistant Faryal Mir。(2017-02-08)
Targeting disease
Finding a reliable way to deliver DNA to target cells could help scientists realize the potential of gene therapy—a method of treating diseases such as cystic fibrosis or hemophilia by delivering new genes that replace missing or defective versions. Another promising approach for new therapies is RNA interference, which can be used to turn off overactive genes by blocking them with short strands of RNA known as siRNA.
找到可靠的将DNA运载到靶细胞的方式可以帮助科研工作者们认识到基因疗法--一种通过运载新的基因来囊肿性纤维化、血友病等疾病的方法--替代丢失或有缺陷的基因来治疗的潜力。新疗法的另一种有前景的实现方式是RNA干预，RNA干预通过用一小段RNA，即siRNA，来阻碍过于活跃的基因的表达。
Delivering these types of genetic material into body cells has proven difficult, however, because the body has evolved many defense mechanisms against foreign genetic material such as viruses.
运载这些基因材料到体内细胞中十分困难，毕竟人体进化出了很多防御机制来抵抗病毒等外来基因材料。
To help evade these defenses, Anderson's lab has developed nanoparticles, including many made from fatty molecules called lipids, that protect genetic material and carry it to a particular destination. Many of these particles tend to accumulate in the liver, in part because the liver is responsible for filtering blood, but it has been more difficult to find particles that target other organs.
为了避开这些防御机制，Anderson实验室开发出了纳米颗粒，其中很多从脂类制得，来保护基因材料，并携带其到目的地。这些颗粒中有许多都倾向于再肝脏积聚，这部分上因为肝脏负责过滤血液，但这样就更难以发现瞄准其他器官的颗粒。
"We've gotten good at delivering nanoparticles into certain tissues but not all of them," Anderson says. "We also haven't really figured out how the particles' chemistries influence targeting to different destinations."
“我们已经善于把纳米颗粒运载到特定组织，但并非所有组织，”Anderson说。“我们也还没有弄清颗粒的化学性质如何影响其瞄准的目标。”(2017-02-12)
To identify promising candidates, Anderson's lab generates libraries of thousands of particles, by varying traits such as their size and chemical composition. Researchers then test the particles by placing them on a particular cell type, grown in a lab dish, to see if the particles can get into the cells. The best candidates are then tested in animals. However, this is a slow process and limits the number of particles that can be tried.
为了发现有潜力的候选颗粒，Anderson实验室通过改变粒径、化学组成，开发了包含数千颗粒的库。然后研究者将它们放置在特定细胞类型上，在培养皿中培养，来看颗粒是否可以长到细胞中。之后用表现最好的候选颗粒作动物实验。然而，这是一个缓慢的过程，并且限制了可试验的颗粒数量。
"The problem we have is we can make a lot more nanoparticles than we can test," Anderson says.
To overcome that hurdle, the researchers decided to add "barcodes," consisting of a DNA sequence of about 60 nucleotides, to each type of particle. After injecting the particles into an animal, the researchers can retrieve the DNA barcodes from different tissues and then sequence the barcodes to see which particles ended up where.
“我们的问题是我们能制造的颗粒数目比我们能测试的多太多，”Anderson说。为克服这个障碍，研究人员决定加入“条码”，其由一段约60个核苷酸的DNA序列组成。在将颗粒注入到动物后，研究人员从各组织中回收DNA条码，再测定条码序列来弄清颗粒最终停留在哪。
"What it allows us to do is test many different nanoparticles at once inside a single animal," Dahlman says.
“这种方法允许我们在一个动物中同时测试多个不同纳米颗粒，”Dahlman说。
Tracking particles
追踪颗粒
The researchers first tested particles that had been previously shown to target the lungs and the liver, and confirmed that they did go where expected.
研究人员首先测试先前显示把肺脏和肝脏作为目标的颗粒，确认它们是否去向期望的组织。
Then, the researchers screened 30 different lipid nanoparticles that varied in one key trait—the structure of a component known as polyethylene glycol (PEG), a polymer often added to drugs to increase their longevity in the bloodstream. Lipid nanoparticles can also vary in their size and other aspects of their chemical composition.
然后，研究人员筛选了30种不同脂类颗粒，它们只在一个关键特点上不同--那就是其成分聚乙二醇(PEG)的结构，聚乙二醇经常被加入到药物中来延长其在血流中的寿命。脂类纳米颗粒也可以改变其粒径，和其他化学成分。
Each of the particles was also tagged with one of 30 DNA barcodes. By sequencing barcodes that ended up in different parts of the body, the researchers were able to identify particles that targeted the heart, brain, uterus, muscle, kidney, and pancreas, in addition to liver and lung. In future studies, they plan to investigate what makes different particles zero in on different tissues.
每个纳米颗粒也用一个30DNA条码标记。通过测序条码最终在身体中的位置，除了肝脏和肺脏，研究人员还能够发现指向心脏、脑、子宫、肌肉、肾脏和胰腺的颗粒。在未来的研究中，他们计划研究使不同颗粒瞄准不同组织的机理。
The researchers also performed further tests on one of the particles, which targets the liver, and found that it could successfully deliver siRNA that turns off the gene for a blood clotting factor.
研究人员也在对其中瞄准肝脏的颗粒做进一步的研究，发现其可以顺利地运载可以关闭凝血因子基因的siRNA。
Victor Koteliansky, director of the Skoltech Center for Functional Genomics, described the technique as an "innovative" way to speed up the process of identifying promising nanoparticles to deliver RNA and DNA.
Victor Koteliansky，Skoltech Center for Functional Genomics的负责人，评论这一技术是一种创新方式，加速了鉴别潜在的运载RNA和DNA的纳米颗粒。
"Finding a good particle is a very rare event, so you need to screen a lot of particles. This approach is faster and can give you a deeper understanding of where particles will go in the body," says Kotelianksy, who was not involved in the research.
“找到一个优良的颗粒是极稀少的事件，因此你需要筛选很多颗粒。这一方法快速，可以使你更深入地理解颗粒将进入身体的哪个组织，”没有参加这一研究的Kotelianksy说。
This type of screen could also be used to test other kinds of nanoparticles such as those made from polymers. "We're really hoping that other labs across the country and across the world will try our system to see if it works for them," Dahlman says.
这一筛选方法也可以用于测试其他种类的纳米颗粒，例如由多聚物制备的纳米颗粒。“我们非常希望国内外其他实验室测试我们的系统对他们是否有效，”Dahlman说。(2017-02-12)