How a new nano-delivery system can help antibiotics avoid "misinjuring" intestinal flora

Guided reading

Antibiotics have the advantages of broad-spectrum antibacterial effect, low production cost, and convenient use.
Therefore, they are widely used in the treatment of various bacterial infections.
Antibiotics are the cornerstone of antibacterial infection treatment
.

However, antibiotics are a coin with both sides.
Oral broad-spectrum antibiotics will seriously damage the homeostasis of intestinal flora while killing pathogenic bacteria, which will lead to intestinal flora imbalance and related diseases.
, the emergence of an increasing number of broad-spectrum drug-resistant bacteria poses a major challenge to modern medicine
.

On August 4, 2022, Zhang Guorong, a postdoctoral fellow in the laboratory of Prof.
Zhu Shu at the Chinese University of Science and Technology, introduced a brand new antibiotic delivery system to us at the "Young Ke Salon" event, mainly discussing the use of this system in the process of oral antibiotics in the treatment of bacterial infections.
, How to help avoid "accidentally hurt" intestinal bacteria, effectively protect intestinal homeostasis, and achieve the best of both worlds
.

We take oral antibiotics to treat bacterial infections every day.
While protecting ourselves from bacterial infections, we also accidentally harm the intestinal flora
.
How to effectively protect intestinal homeostasis is a major problem that needs to be solved urgently in the field of bacterial infection treatment
.

On July 7, 2022, Professor Zhu Shu and the team of Professor Wang Yucai published a paper entitled "Glucosylated nanoparticles for the oral delivery of antibiotics to the proximal small intestine" in the journal "Nature Biomedical Engineering".
protect mice from gut dysbiosis"
.

Screenshot of the paper

This study developed a novel delivery vehicle for oral antibiotics, which can efficiently promote the absorption of oral antibiotics while effectively reducing the disruption of antibiotics to intestinal flora homeostasis
.
At present, the research results have been applied for national and PCT invention patents
.

So how was this delivery vehicle developed? The research team designed and synthesized glucose-modified cationic nanocarriers (PGNPs) to deliver antibiotics by taking advantage of the high expression of sodium ion-dependent glucose transporter 1 (SGLT1) in the proximal small intestine
.
The glucose molecules on the surface of PGNPs can specifically bind to SGLT1 in the proximal small intestine, and the cations on the surface can help the nanocarriers penetrate the mucosal layer, thereby targeting the epithelial cells of the small intestine and improving the delivery efficiency
.

Studies have found that antibiotics encapsulated by PGNPs can bind to SGLT1 at the front of the small intestine, and efficiently deliver antibiotics such as ampicillin and chloramphenicol into the blood circulation through ligand-receptor-mediated endocytosis and transcytosis
.
PGNPs, a delivery vehicle, can increase the bioavailability of antibiotics, thereby effectively treating pulmonary bacterial infections and Listeria systemic infections
.

The research team further confirmed that oral PGNPs-encapsulated antibiotics significantly reduced the risk of diseases caused by antibiotic-related intestinal flora disturbances, such as intestinal opportunistic pathogen infection and metabolic disease obesity, and reduced intestinal drug resistance.
Accumulation of antibiotic resistance genes in bacteria and symbionts
.

This research is expected to avoid the two major side effects of current oral antibiotics on the human body: destruction of intestinal flora causing chronic diseases and the accumulation of intestinal drug-resistant bacteria and drug-resistant genes
.

What do industry experts say about this research result? Academician Li Lanjuan, professor of Zhejiang University and academician of the Chinese Academy of Engineering, said that the work of Zhu Shu's team has developed a novel oral delivery of antibiotics encapsulated by glycosylated cationic nanoparticles (PGNPs) in response to many clinical and social problems caused by oral antibiotics.
way
.
This novel nanoparticle-encapsulated antibiotic is expected to replace the current oral administration of common antibiotics to a considerable extent
.

Li Zhaoshen, a professor at the Naval Military Medical University and an academician of the Chinese Academy of Engineering, said that it is an important scientific issue to develop a new type of antibiotic administration method and dosage form that is convenient, efficient, accurate in positioning and can prevent the destruction of intestinal flora
.
This work also suggests that the nanoparticles may be used to encapsulate more orally delivered drugs, such as those that are difficult to dissolve, easily degrade, or otherwise disrupt the gut microbiota, which are worthy of further exploration
.
This study puts forward new ideas for solving the side effects caused by oral antibiotics, and has important clinical translation potential
.

Zhang Guorong, a postdoctoral fellow at the University of Science and Technology of China

Next, we will present how Dr.
Leslie Cheung explained the characteristics of this delivery system and its future application direction by means of question and answer
.

Q: During the experiment, do you conduct research on the toxic and side effects of this delivery system, and will it have any potential safety hazards?

A: During our research on this topic, we also tested its security
.
First, after oral administration of PGNPs nanoparticles to mice, we observed the proportion of blood cells such as white blood cells, red blood cells, and platelets in mice, and also detected the relevant indicators of liver function and kidney function in mice.
The test results show that, These indicators are within the normal range after administration, which means that the delivery particle is very safe in mice
.
At the same time, the monomers used in this nanoparticle such as PLGA (polylactic-co-glycolic acid) are FDA-certified, and others such as PEG and cationic liposome DOTAP are also a common molecule used for drug modification.
Therefore, We believe that this nanoparticle is not toxic
.

Q: What is the delivery efficiency of PGNP-glycosylated cationic nanoparticles? After the patient takes it, what is its half-life in the human body, and will it always exist in the human circulatory system?

A: It does not always exist in the human body
.
After these nanoparticles are ingested by mice, they will be degraded into some biosoluble substances in about 8-12 hours
.
The experimental results show that the nanoparticle can encapsulate hydrophilic penicillin and hydrophobic chloramphenicol, etc.
It has better encapsulation effect on chloramphenicol, so we guess that it has better encapsulation ability for hydrophobic drugs
.
In terms of delivery efficiency, compared with traditional oral antibiotics, the drug residue in the intestine is close to 100% after four hours of oral ampicillin, while the drug residue in feces and cecum is about 3% after using nanoparticle PGNP.
%, and the percentage in the blood reaches about 43%
.

Q: In addition to delivering antibiotics, could this nanoparticle be used to deliver other drugs? Will it be applied in the future?

A: This nanoparticle can actually be used to encapsulate some insoluble substances, or some drugs that are irritating to the gut and intestinal flora
.
By its nature, it can be encapsulated for some small molecule drugs
.
After the current part of this project is over, we will also contact our collaborators and some hospital departments to try to apply these results to scientific research or clinical practice.
Later, we will continue to solve the stability, encapsulation rate and encapsulation of the nanoparticles.
types of antibiotics,
etc.