Monday, October 2, 2023

How CRISPR and chemotherapy join forces to fight tumors

The fight against cancer has taken many forms. These approaches include treatments such as chemotherapy, gene therapy, radiation therapy, and immunotherapy, to name a few, but cancer cells have proven to be quite resistant to these methods.

Now, in a recent study, researchers are combining two known treatments to create a promising new therapy.

A promising combination

A well-known chemotherapy drug called Take It shrinks tumors by killing cancer cells. However, the body’s cancer cells are surrounded by a multitude of other cell types, all dedicated to promoting tumor growth and thwarting threats from cancer therapies. These external cells can significantly hinder the success of olaparib. Furthermore, the notorious side effects of chemotherapy are due in part to the indiscriminate destruction of healthy cells.

The advent of the CRISPR/Cas9 system for gene editing has heralded an alternative strategy for targeting tumors, which aims to personalize cancer treatment and minimize off-target effects.

The CRISPR/Cas9 system was originally extracted from bacteria and works like molecular scissors. The complex consists of the Cas9 enzyme, which can cut a cell’s genetic information, and a molecular tag that specifies the exact location where the genetic information should be changed. This allows researchers to add or delete sections of genetic information, at specific locations, in living systems.

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In cancer treatment, genome editing has been used to modify genetic information to support and increase treatment response against cancer cells. This is particularly useful against genetically based cancers, such as certain types of breast cancer caused by a mutation in the BRCA discomfort.

However, cancer cells are a difficult target for gene editing therapy. Classified as a complex disease, cancer not only has a single genetic origin, but is also influenced by environmental and lifestyle factors.

Looking for ways to harness the benefits of these two treatments, researchers came up with the idea of ​​combining them.

To make the puzzle

A recent study in advanced science describes a strategy to inhibit breast cancer tumors using CRISPR/Cas9 linked to chemotherapy, in a new special formulation designed to address these challenges in tumor treatment.

Previous attempts to coadminister CRISPR/Cas9 with chemical drugs have shown that different formulations can lead to toxicity of the therapeutic combination, without notable positive additive effects. However, physically linking CRISPR/Cas9 to the drug Olaparib required careful consideration. Since the two are very different and contain different elements, it is difficult to group them together.

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This is where nanocomplexes come into play. Generally composed of several biological molecules grouped in a nanometric-sized complex, they constitute a commonly used tool to increase cell penetration. In this case, the nanocomplexes were formed by attaching Cas9-Olaparib to a third molecule called polyethyleneimine or PEI.

“When PEI is conjugated with Cas9, effective delivery can be achieved with minimal toxicity,” explained Hyun Jung Chung, associate professor in the Department of Biological Sciences at the Korea Advanced Institute of Science and Technology (KAIST) and principal investigator of the study. . an email. “The formation of nanocomplexes is necessary for effective introduction into cells. Without the formation of nanocomplexes, internalization into cells would not be possible.

ComBiNE: New hope for cancer treatment

The group called the resulting therapy “combinatorial and bioorthogonal nanoediting complex,” or ComBiNE for short. When injected into mouse tumors for 24 days, ComBiNE was able to penetrate and destroy cancer cells, reducing tumor growth by 70% compared to untreated tumors. Control studies showed that the complex worked better than either component alone, highlighting the synergistic effects of the new system.

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ComBiNE also showed promise in terms of side effects. “The formulation in our study is specific to breast cancer cells. BRCA mutation. The drug conjugated to the Cas9 protein (Olaparib) has an effect on these cancer cells, not other normal cells,” Chung said.

The focus is now on optimizing ComBiNE for application in clinical settings. “The CRISPR/Cas conjugate system is advantageous because it allows efficient delivery with only a minimal amount of carrier material, resulting in low toxicity,” Chung explained. “While we have demonstrated promising data for local delivery, our goal is to further improve the technology that will be applied for systemic delivery. »

Without being limited to the building blocks used in this study, ComBiNE can be created from a wide variety of molecules to treat a variety of human diseases, providing a versatile tool for further biopharmaceutical development and highlighting a novel anti-cancer approach.

Reference: Park Hee-Sung, Hyun Jung Chung, et al., Bioorthogonal CRISPR/Cas9-drug conjugate: a combinatorial nanomedicine platform, Advanced Sciences (2023). DOI: 10.1002/adv.202302253

Cover image: The National Cancer Institute on Unsplash

2023-09-19 11:48:02
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