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如何使更多的抗癌纳米粒子到达需要的地方

信息来源:星火计划 发布时间:【2020-08-14 】 点击次数:
确定该阈值提供了一种潜在的通用方法,可用于衡量纳米粒子的剂量,并且可以帮助推进新一代的癌症治疗,成像和诊断。
MD / Ph.D说:“这是一个非常简单的解决方案,可以调整剂量,但结果非常有效。” 候选人本·欧阳(Ben Ouyang),在陈华伦(Warren Chan)教授的指导下领导了这项研究。
 
他们的发现今天发表在《自然材料》上,为四年前由Chan和研究人员在《自然评论材料》上提出的药物输送问题提供了解决方案。
 
纳米技术载体可用于将药物运送到癌症部位,进而有助于患者对治疗的反应并减少不良副作用,例如脱发和呕吐。然而,实际上,几乎没有注射的颗粒到达肿瘤部位。
 
研究小组在《自然评论材料》(Nature Reviews Materials)论文中对过去十年的文献进行了调查,结果发现,就中位数而言,只有0.7%的化学治疗性纳米颗粒使其成为目标肿瘤。
 
Chan解释说:“新兴疗法的前景取决于我们将其运送到目标部位的能力。” “我们发现了增强递送过程的新原理。这对于纳米技术,基因组编辑器,免疫疗法和其他技术而言可能是重要的。”
 
Chan的团队将过滤血液的肝脏视为阻碍纳米颗粒药物输送的最大障碍。他们假设肝脏将具有吸收率阈值-换句话说,一旦器官被纳米颗粒饱和,就无法跟上更高的剂量。他们的解决方案是控制剂量以淹没排列在肝脏通道中的器官过滤性库普弗细胞。
 
研究人员发现,在体内向小鼠体内注入1万亿个纳米颗粒的基线足以淹没细胞,因此它们无法足够快地吸收颗粒以适应不断增加的剂量。结果是向肿瘤的递送效率为12%。
 
欧阳说:“要增加12%,还有许多工作要做,但与0.7相比,这是很大的一步。” 研究人员还广泛测试了压倒性的库普弗细胞是否会导致肝脏,心脏或血液中任何毒性的风险。
 
欧阳说:“我们测试了金,二氧化硅和脂质体。” “在我们所有的研究中,无论我们推高剂量,我们都从未见过任何毒性迹象。”
 
研究小组利用这一阈值原理来提高临床使用的,装有化学疗法的纳米颗粒Caelyx的有效性。与单独使用化疗药物多柔比星的Caelyx相比,他们的策略可将肿瘤缩小60%以上。
 
由于研究人员的解决方案很简单,因此他们希望看到该阈值甚至在当前用于人体临床试验的纳米剂量给药惯例中也具有积极意义。他们计算出人类阈值约为1.5万亿个纳米颗粒。
 
Chan说:“ 这种方法很简单,它表明我们不必重新设计纳米颗粒就可以提高传输效率。” “这可以解决一个主要的交付问题。”


英文版:
             

How to get more cancer-fighting nanoparticles to where they are needed


University of Toronto Engineering researchers have discovered a dose threshold that greatly increases the delivery of cancer-fighting drugs into a tumor.
 
 
Determining this threshold provides a potentially universal method for gauging nanoparticle dosage and could help advance a new generation of cancer therapy, imaging and diagnostics.
 
"It's a very simple solution, adjusting the dosage, but the results are very powerful," says MD/Ph.D. candidate Ben Ouyang, who led the research under the supervision of Professor Warren Chan.
 
Their findings were published today in Nature Materials, providing solutions to a drug-delivery problem previously raised by Chan and researchers four years ago in Nature Reviews Materials.
 
Nanotechnology carriers are used to deliver drugs to cancer sites, which in turn can help a patient's response to treatment and reduce adverse side effects, such as hair loss and vomiting. However, in practice, few injected particles reach the tumor site.
 
In the Nature Reviews Materials paper, the team surveyed literature from the past decade and found that on median, only 0.7 percent of the chemotherapeutic nanoparticles make it into a targeted tumor.
 
"The promise of emerging therapeutics is dependent upon our ability to deliver them to the target site," explains Chan. "We have discovered a new principle of enhancing the delivery process. This could be important for nanotechnology, genome editors, immunotherapy, and other technologies."
 
Chan's team saw the liver, which filters the blood, as the biggest barrier to nanoparticle drug delivery. They hypothesized that the liver would have an uptake rate threshold—in other words, once the organ becomes saturated with nanoparticles, it wouldn't be able to keep up with higher doses. Their solution was to manipulate the dose to overwhelm the organ's filtering Kupffer cells, which line the liver channels.
 
The researchers discovered that injecting a baseline of 1 trillion nanoparticles in mice, in vivo, was enough to overwhelm the cells so that they couldn't take up particles quick enough to keep up with the increased doses. The result is a 12 percent delivery efficiency to the tumor.
 
"There's still lots of work to do to increase the 12 percent but it's a big step from 0.7," says Ouyang. The researchers also extensively tested whether overwhelming Kupffer cells led to any risk of toxicity in the liver, heart or blood.
 
"We tested gold, silica, and liposomes," says Ouyang. "In all of our studies, no matter how high we pushed the dosage, we never saw any signs of toxicity."
 
The team used this threshold principle to improve the effectiveness of a clinically used and chemotherapy-loaded nanoparticle called Caelyx. Their strategy shrank tumors 60 percent more when compared to Caelyx on its own at a set dose of the chemotherapy drug, doxorubicin.
 
Because the researchers' solution is a simple one, they hope to see the threshold having positive implications in even current nanoparticle-dosing conventions for human clinical trials. They calculate that the human threshold would be about 1.5 quadrillion nanoparticles.
 
"There's a simplicity to this method and reveals that we don't have to redesign the nanoparticles to improve delivery," says Chan. "This could overcome a major delivery problem."

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