Large thrust, high load, invisible
nano "rocket" to escort gene drugs directly to the lesion
The polymer carrier system we constructed has the ability of gene and photoacoustic dual-mode imaging, and the function of gene and photothermal combined therapy.
The above-mentioned characteristics make the polymer carrier upgrade from a single function to a multi-function, and have the ability to diagnose and treat tumor tissues as a whole and double-kill.
——Tian Huayu, researcher at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
◎Reporter Yang Lun
The "carrier rocket" is ready to go. It will pass through numerous resistances and accurately assist the "missile" to hit the "bulls-eye"... Is this the scene in the launch site?
No, all this happens at the micro level.
This "rocket" with only about 100 nanometers is a "polymer gene/drug carrier" constructed by Tian Huayu, a researcher at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences and others.
Recently, this research result won the first prize of the 2021 Jilin Province Natural Science Award.
In recent years, scientific researchers have been trying to construct high-efficiency, safe, and low-cost polymer carriers, so that gene therapy, a high-profile medical technology, can take off.
Academician Chen Xuesi of the Changchun Institute of Applied Chemistry of the Chinese Academy of Sciences recognized the importance and urgency of developing high-performance polymer gene carriers as early as 20 years ago.
He once said: "On the one hand, we must do in-depth basic research, analyze basic scientific issues, know what is happening, but also know why. This is a prerequisite to ensure that our research can be at the international leading level. On the other hand, we We must discover problems in actual needs, and we must strive to promote the industrialization and commercialization of polymer gene carriers."
The result of this award is exactly the reward of the 20 years of hard work by the research staff of the institute.
Gene therapy faces the problem of "ammunition" transportation
The essence of gene therapy is to achieve the purpose of curing diseases by regulating genes.
Gene therapy usually requires the construction of therapeutic genes, and then sending these genetic materials into genetically abnormal cells to repair the abnormal genes and produce beneficial proteins.
Since the birth of gene therapy technology in the 1970s, it has been regarded as a revolution in the field of medicine and pharmacy, and it is expected to cure various diseases caused by genetic defects or abnormalities.
After years of technological iteration, renewal, and accumulation, gene therapy has made rapid progress. A batch of breakthrough treatment methods and gene therapy drugs have come out one after another, and a series of clinical results have been achieved.
Because of its outstanding performance, gene therapy has attracted the attention of scientists all over the world.
In the 1990s, scientists from various countries successively carried out relevant research: In 1992, Italian scientists successfully used retroviruses to modify hematopoietic stem cells for the first time. In the following 20 years, the use of gene therapy for hemophilia, solid tumors and leukemia has also been achieved. With positive results, in 2017, the United States approved a second therapy based on the modification of patients’ own immune cells to treat patients with specific lymphoma, and gene therapy once again set off a research boom.
In recent years, the governments of many places in my country have also regarded gene therapy as the key core technology for future scientific and technological innovation and development in their scientific and technological development plans.
But such a miraculous gene therapy faces a key problem: how to deliver genes or drugs to the target.
For example, a powerful weapon lying on a launcher is not lethal.
Take gene therapy for tumors as an example. In order for "ammunition" to work, a "carrier rocket" must be used to deliver it to its destination.
"The human body's environment is more complicated than the atmosphere. It is very difficult to transport modified genes to the cells that need to be treated while avoiding normal cells." Tian Huayu told the Science and Technology Daily reporter.
Polymer carrier guarantees transportation efficiency and safety
For gene therapy, the ideal carrier must not only carry a sufficient amount of genes or drug "ammunition", but also have no toxicity and pathogenicity to the human body and ensure safety; it must be strong enough to protect the "ammunition" from damage The destruction of nucleases must be able to accurately find tumor cells and enter the nucleus.
The polymer carrier is generally a cationic polymer, which has the advantages of safety, low toxicity, easy functionalization, and mass production. However, its low transfection efficiency and lack of intelligent responsiveness are a problem that plagues global researchers.
Tian Huayu led researchers to adopt the strategy of “introducing multiple interactions and synergy” to graft p-toluenesulfonyl-protected arginine on polylysine to obtain a high-performance polymer carrier, allowing electrostatic interaction, Hydrogen bond interactions and hydrophobic interactions work together to make the driving force for the carrier to enter the cell from single to multiple, which greatly increases the efficiency of the carrier to enter the cell.
"This is like upgrading a rocket. It used to be a single-stage rocket. Now we connect multiple rocket engines in series or bundle, which greatly increases the power of the rocket." Tian Huayu said that the polymer carrier can self-assemble into nanoparticles. TEM results show that the assembly of nanoparticles is spherical, with an average size of about 75 nanometers.
What's more interesting is that the researchers also designed a "stealth cloak" for this nano "rocket".
Tian Huayu explained that this is because when the polymer carrier transfers genetic material to the tumor tissue in the body, the circulatory system and the tumor site have contradictory requirements for the physical and chemical properties of the gene carrier.
"The cationic polymer itself has a positive charge. We hope to use the excess positive charge to help it enter the tumor cells, but during transportation, it can easily interact with negatively charged proteins in body fluids or interact with non-target tissue cells. Causes non-specific phagocytosis, which seriously affects the delivery efficiency of complex nanoparticles to target tissues." Tian Huayu said.
Therefore, the researchers cleverly wrapped the "rocket" tightly with dialdehyde-based polyethylene glycol and compressed its volume so that it could deceive the negatively charged proteins in the body and enter the tumor cells efficiently.
After arriving at the destination, this "invisibility cloak" will again "take off" in the special acidic environment of tumor cells.
The carrier is upgraded from a single function to a multi-function
From the practical effect, this new type of polymer carrier realizes the efficient transmission of genetic material in the body, and has achieved exciting effects in anti-tumor therapy.
Experimental results show that using this method, tumor cell endocytosis efficiency and tumor growth inhibition rate are significantly improved.
Not only that, scientific researchers have also introduced detection and combined treatment units into the carrier to build a multifunctional carrier, which improves the ability of real-time monitoring and treatment of diseases.
"The polymer carrier system we have constructed has the capabilities of gene and photoacoustic dual-mode imaging, gene and photothermal combined therapy. The above-mentioned features have upgraded the polymer carrier from a single function to a multi-function, which has integrated diagnosis and treatment of tumor tissues and dual killing Ability." Tian Huayu said.
The polymer carrier combined with the shielding system, loaded with genetic material, protein, and chemotherapeutic drugs, becomes a universal carrier platform.
Using this platform, Tian Huayu and others have further constructed a nano-drug delivery system based on two tumor acidic microenvironment responses—chemotherapeutic drug loading system and gene loading system, and then developed a new type of immune cocktail therapy.
The therapy has shown excellent therapeutic efficacy in several tumor models.
Localization of gene transfection reagents breaks foreign monopoly
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From the beginning of Chen Xuesi's deployment of efficient gene therapy vectors 20 years ago, industrialization and commercialization have been one of the main goals of this technology.
Although it will take some time for gene vectors to move towards clinical treatment, the time for industrialization of gene transfection reagents is ripe.
As a key link in gene therapy, the core technology of gene transfection reagents has always been monopolized by foreign companies.
In view of this, under the encouragement and leadership of Chen Xuesi, and with the strong support of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Jilin Provincial Department of Science and Technology, Researcher Tian Huayu has been devoted to the research and development of gene transfection reagents for 20 years. In the work, on the basis of previous research, we are determined to innovate, overcome difficulties, and completely get rid of the difficult predicament of being constrained by others in this field.
"The breakthroughs made in domestic gene transfection reagents have allowed my country to change the status quo of reliance on imports of gene transfection reagents." Tian Huayu said.
At present, the research team has successfully developed 3 varieties of gene transfection reagents and is gradually expanding the market. It has been used in more than 50 universities, hospitals and scientific research institutions.