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Lipid nanoparticles carry gene-editing cancer drugs past tumor defenses

As they grow, solid tumors surround themselves with a thick, hard-to-penetrate wall of molecular defenses. Getting drugs past that barricade is notoriously…

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As they grow, solid tumors surround themselves with a thick, hard-to-penetrate wall of molecular defenses. Getting drugs past that barricade is notoriously difficult. Now, scientists at UT Southwestern have developed nanoparticles that can break down the physical barriers around tumors to reach cancer cells. Once inside, the nanoparticles release their payload: a gene editing system that alters DNA inside the tumor, blocking its growth and activating the immune system.

Credit: UT Southwestern Medical Center

As they grow, solid tumors surround themselves with a thick, hard-to-penetrate wall of molecular defenses. Getting drugs past that barricade is notoriously difficult. Now, scientists at UT Southwestern have developed nanoparticles that can break down the physical barriers around tumors to reach cancer cells. Once inside, the nanoparticles release their payload: a gene editing system that alters DNA inside the tumor, blocking its growth and activating the immune system.

The new nanoparticles, described in Nature Nanotechnology, effectively stopped the growth and spread of ovarian and liver tumors in mice. The system offers a new path forward for the use of the gene editing tool known as CRISPR-Cas9 in cancer treatment, said study leader Daniel Siegwart, Ph.D., Associate Professor of Biochemistry at UT Southwestern. 

“Although CRISPR offers a new approach for treating cancer, the technology has been severely hindered by the low efficiency of delivering payloads into tumors,” said Dr. Siegwart, a member of the Harold C. Simmons Comprehensive Cancer Center.

In recent years, CRISPR-Cas9 technology has given researchers a way to selectively edit the DNA inside living cells. While the gene editing system offers the potential to alter genes that are driving cancer growth, delivering CRISPR-Cas9 to solid tumors has been challenging.

For more than a decade, Dr. Siegwart and his colleagues have been studying and designing lipid nanoparticles (LNPs), small spheres of fatty molecules which can carry molecular cargo (including recent mRNA COVID-19 vaccines) into the human body. In 2020, Dr. Siegwart’s group showed how to direct nanoparticles to specific tissues, which had been a challenge limiting the field.

In the new work, to target cancer, the researchers began with the nanoparticles that they had already optimized to travel to the liver. They added a small piece of RNA (called short interfering RNA or siRNA) that could shut off focal adhesion kinase (FAK), a gene that plays a central role in holding together the physical defenses of a number of tumors.

“Targeting FAK not only weakens the barricade around tumors and makes it easier for the nanoparticles themselves to make their way into the tumor, but also paves the way to allow immune cells in,” said Di Zhang, Ph.D., a postdoctoral research fellow at UTSW and first author of the paper.

Inside the newly engineered nanoparticles, the researchers encapsulated CRISPR-Cas9 machinery that could edit the gene PD-L1. Many cancers use this gene to produce high levels of the PD-L1 protein, which puts the brakes on the immune system’s ability to attack tumors. Scientists have previously shown that disrupting the PD-L1 gene, in some cancers, can lift those brakes and enable a person’s immune system to kill cancer cells.

Drs. Siegwart, Zhang, and their colleagues tested the new nanoparticles in four mouse models of ovarian and liver cancer. They first showed that by adding siRNA to shut off FAK, the matrix of molecules around the tumors was less stiff and easier to penetrate than normal. Then, they analyzed the tumor cells and found that many more nanoparticles had reached the cells, effectively altering the PD-L1 gene.

Finally, they found that tumors in mice treated with the nanoparticles that targeted both FAK and PD-L1 shrank to about one-eighth the size of tumors treated only with empty nanoparticles. In addition, more immune cells infiltrated the tumors and the treated mice survived, on average, about twice as long. 

More work is needed to show the safety and efficacy of the nanoparticles in a variety of tumor types. The researchers said the therapy may be useful in conjunction with existing cancer immunotherapies that aim to use the immune system to attack tumors.

“After the worldwide success of the COVID-19 LNP vaccines, we are all wondering what else LNPs can do. Here we developed new LNPs capable of delivering multiple kinds of genetic drugs simultaneously to improve therapeutic outcomes in cancer. There is clearly great potential for LNP medicines to treat different kinds of diseases,” said Dr. Siegwart.

Other researchers who contributed to this study include Guoxun Wang, Xueliang Yu, Tuo Wei , Lukas Farbiak , Lindsay T. Johnson of UTSW and Hao Zhu of the Children’s Medical Research Institute at UTSW and Alan Mark Taylor, Jiazhu Xu and Yi Hong  of UT Arlington.

Dr. Siegwart is a co-founder and consultant for ReCode Therapeutics, which has licensed intellectual property from UT Southwestern.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.


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China Suggests It Could Maintain ‘Zero COVID’ Policy For 5 Years

China Suggests It Could Maintain ‘Zero COVID’ Policy For 5 Years

Authored by Paul Joseph Watson via Summit News,

China has suggested it will…

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China Suggests It Could Maintain 'Zero COVID' Policy For 5 Years

Authored by Paul Joseph Watson via Summit News,

China has suggested it will maintain its controversial ‘zero COVID’ policy for at least 5 years, eschewing natural immunity and guaranteeing repeated rounds of new lockdowns.

“In the next five years, Beijing will unremittingly grasp the normalization of epidemic prevention and control,” said a story published by Beijing Daily.

The article quoted Cai Qi, the Communist Party of China’s secretary in Beijing and a former mayor of the city, who said that ‘zero COVID’ approach would remain in place for 5 years.

After the story prompted alarm, reference to “five years” was removed from the piece and the hashtag related to it was censored by social media giant Weibo.

“Monday’s announcement and the subsequent amendment sparked anger and confusion among Beijing residents online,” reports the Guardian.

“Most commenters appeared unsurprised at the prospect of the system continuing for another half-decade, but few were supportive of the idea.”

Although western experts severely doubt official numbers coming out of China, Beijing claimed success in limiting COVID deaths by enforcing the policy throughout 2021.

However, this meant that China never achieved anything like herd immunity, and at one stage the Omicron variant caused more more coronavirus cases in Shanghai in four weeks than in the previous two years of the entire pandemic.

Back in May, World Health Organization Director General Tedros Adhanom Ghebreyesus suggested that China would be better off if it abandoned the policy, but Beijing refused to budge.

As we previously highlighted, the only way of enforcing a ‘zero COVID’ policy is via brutal authoritarianism.

In Shanghai, children were separated from their parents in quarantine facilities and others were left without urgent treatment like kidney dialysis.

Panic buying of food also became a common occurrence as the anger threatened to spill over into widespread civil unrest.

Former UK government COVID-19 advisor Neil Ferguson previously admitted that he thought “we couldn’t get away with” imposing Communist Chinese-style lockdowns in Europe because they were too draconian, and yet it happened anyway.

“It’s a communist one party state, we said. We couldn’t get away with it in Europe, we thought,” said Ferguson.

“And then Italy did it. And we realised we could,” he added.

*  *  *

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Tyler Durden Tue, 06/28/2022 - 18:05

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No sign of major crude oil price decline any time soon

Bullish pressure on crude oil markets doesn’t seem to be easing Crude oil prices fell last week, notching their second weekly decline in the face of…

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Bullish pressure on crude oil markets doesn’t seem to be easing

Crude oil prices fell last week, notching their second weekly decline in the face of concern that rising interest rates could push the global economy into recession.

Yet the future of crude oil still seems bullish to many. Spare capacity, or lack of it, is just one of the reasons.

The global surplus of crude production capacity in May was less than half the 2021 average, the U.S. Energy Information Administration (EIA) reported on Friday.

The EIA estimated that as of May, producers in nations not members of the Organization of Petroleum Exporting Countries (OPEC) had about 280,000 barrels per day (bpd) of surplus capacity, down sharply from 1.4 million bpd in 2021. It said 60 per cent of the May 2021 figure was from Russia, which is increasingly under sanctions related to its invasion of Ukraine.

The OPEC+ alliance of oil producers is running out of capacity to pump crude, and that includes its most significant member, Saudi Arabia, Nigerian Minister of State for Petroleum Resources Timipre Sylva told Bloomberg last week.

“Some people believe the prices to be a little bit on the high side and expect us to pump a little bit more, but at this moment there is really little additional capacity,” Sylva said in a briefing with reporters on Friday. “Even Saudi Arabia, Russia, of course, Russia, is out of the market now more or less.” Nigeria was also unable to fulfil its output obligations, added Sylva.

Recent COVID-19-related lockdowns in parts of China – the world’s largest crude importer – also played a significant role in the global oil dynamics. The lack of Chinese oil consumption due to the lockdowns helped keep the markets in a check – somewhat.

Oil prices haven’t peaked yet because Chinese demand has yet to return to normal, a United Arab Emirates official told a conference in Jordan early this month. “If we continue consuming, with the pace of consumption we have, we are nowhere near the peak because China is not back yet,” UAE Energy Minister Suhail Al-Mazrouei said. “China will come with more consumption.”

Al-Mazrouei warned that without more investment across the globe, OPEC and its allies can’t guarantee sufficient supplies of oil as demand fully recovers from the pandemic.

But the check on the Chinese crude consumption seems to be easing.

On Saturday, Beijing, a city of 21 million-plus people, announced that primary and secondary schools would resume in-person classes. And as life seemed to return to normal, the Universal Beijing Resort, which was closed for nearly two months, reopened on Saturday.

Chinese economic hub Shanghai, with a population of 28 million-plus people, also declared victory over COVID after reporting zero new local cases for the first time in two months.

The two major cities were among several places in China that implemented curbs to stop the spread of the omicron wave from March to May.

But the easing of sanctions should mean oil’s price trajectory will resume its upward march.

In the meantime, in the U.S., the Biden administration is eying tougher anti-smog requirements. According to Bloomberg, that could negatively impact drilling across parts of the Permian Basin, which straddles Texas and New Mexico and is the world’s biggest oil field.

While the world is looking for clues about what the loss of supply from Russia will mean, reports are pouring in that the ongoing political turmoil in Libya could plague its oil output throughout the year.

The return of blockades on oilfields and export terminals amid renewed political tension is depriving the market of some of Libya’s oil at a time of tight global supply, said Tsvetana Paraskova in a piece for Oilrpice.com.

And in the ongoing political push to strangle Russian energy output, the G7 was reportedly discussing a price cap on oil imports from Russia. Western countries are increasingly frustrated that their efforts to squeeze out Russian energy supplies from the markets have had the counterproductive effect of driving up the global crude price, which is leading to Russia earning more money for its war chest.

To tackle the issue, and increase pressure on Russia, U.S. Treasury Secretary Janet Yellen is proposing a price cap on Russian crude oil sales. The idea is to lift the sanction on insurance for Russian crude cargo for countries that accept buying Russian oil at an agreed maximum price. Her proposal is aimed at squeezing Russian crude out of the market as much as possible.

So the bullish pressure on crude oil markets doesn’t seem to be easing.

By Rashid Husain Syed

Toronto-based Rashid Husain Syed is a respected energy and political analyst. The Middle East is his area of focus. As well as writing for major local and global newspapers, Rashid is also a regular speaker at major international conferences. He has provided his perspective on global energy issues to the Department of Energy in Washington and the International Energy Agency in Paris.

Courtesy of Troy Media

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WTI Extends Gains After Unexpected Crude Draw

WTI Extends Gains After Unexpected Crude Draw

Oil prices are higher today following relatively positive news from China (easing some of its…

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WTI Extends Gains After Unexpected Crude Draw

Oil prices are higher today following relatively positive news from China (easing some of its COVID quarantine restrictions), Macron-inspired doubts over the ability of Saudi Arabia and the United Arab Emirates to significantly boost output, and unrest in Ecuador and Libya helped lift prices.

“We’re in the crunch period, it’s hard to see any meaningful price relief for crude,” said John Kilduff.

There’s a lot of strength with China relaxing its Covid restrictions and starting its independent refiners, “we’re going to have another chunk of demand for crude oil,” as China relaxes its Covid-19 restrictions.

With no EIA data released last week due to a "systems issue" (they have issued a statement confirming that the data - and the newest data - will both be released tomorrow), the only guidance we have for now on the past week's inventory changes is from API...

API (last week)

  • Crude +5.607mm

  • Cushing -390k

  • Gasoline +1.216mm - first build since March

  • Distillates -1.656mm

API (this week)

  • Crude -3.799mm

  • Cushing -650k

  • Gasoline +2.852mm

  • Distillates +2.613mm

Crude stocks unexpectedly fell last week, almost erasing the major build from the week before (according to API). Gasoline stocks rose for the second straight week

Source: Bloomberg

WTI was hovering around $111.75 and pushed up to $112 after the unexpected crude draw...

Finally, we note that the tight supply situation in oil (especially European) is revealing itself in the WTI-Brent spread, grew to $6.19, the widest in almost three months.

“European demand will remain robust, especially as natural gas supplies run out, while the North American demand for crude is weakening,” said Ed Moya, senior market analyst at Oanda.

This is not good news for President Biden as prices are rising...

And his ratings are hitting record lows.

Tyler Durden Tue, 06/28/2022 - 16:37

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