Gene therapy for brain cancer: new successes

An international team of researchers working under the leadership of Dr. Jordan Green from Johns Hopkins University has developed a new nanoparticle-based delivery system for therapeutic genes for gene therapy. Its use has significantly increased the life expectancy of glioma model rats.

Glioma is one of the most unfavorable oncological diagnoses in humans. The five-year survival rate for this disease, which has no effective treatment methods, is only 12%. Advances in the study of molecular processes leading to tumor development have formed the basis for the development of therapies based on the delivery of genes to malignant cells, whose protein products kill the tumor or inhibit its growth. However, modern approaches imply the use of viral vectors for gene delivery, the introduction of which into the body can cause serious side effects, such as toxic effects, activation of the immune system against the virus and the formation of new tumors under the influence of the virus.

Fig. 1. The scheme of gene therapy using nanoparticles.

A. Nanoparticles are injected into the glioma-carriers of DNA encoding the HSVtk gene.

B. Convection delivery under pressure ensures the distribution of nanoparticles (yellow dots) throughout the tumor volume (pink).

With. Nanoparticles provide the production of the enzyme thymidine kinase, which spreads throughout the tumor (yellow).

D. Ganciclovir injected into the bloodstream reacts with thymidine kinase, which leads to the death of malignant cells and a decrease in the size of the tumor.

Recent studies have demonstrated the possibility of using biodegradable nanoparticles to deliver genes inside cells. This avoids many of the problems associated with the introduction of viral vectors. The authors decided to use this approach to deliver the HSVtk gene inside tumor cells. The enzyme thymidine kinase encoded by this gene turns the drug ganciclovir, harmless to tumor cells, into a compound toxic to rapidly dividing glioma cells.

Fig. 2. Nanoparticles injected by the method of convection delivery into the brain of rats are distributed throughout the tumor volume.

A. In the upper left part of the section of rat brain tissue, a glioma (purple) is visible.

B. Test nanoparticles labeled with a fluorescent protein, after injection by convection delivery, spread throughout the entire volume of the tumor.

In experiments on cell lines, the authors tested the ability of several types of polymer nanoparticles to deliver DNA to glioma cells and found that the most effective are nanoparticles made of PBAE 447 polymer. Moreover, when combined with ganciclovir, HSVtk-coding nanoparticles ensured the destruction of 100% of the cells of the two glioma lines used by the authors.

At the next stage of the work, the new approach was tested on a rat model of glioma. To ensure the spread of nanoparticles throughout the tumor volume, the authors used the method of convection delivery, which consists in applying a pressure gradient during the introduction of nanoparticles.

As part of the experiment, rats received systemic injections of ganciclovir for two days, after which therapeutic nanoparticles were injected into their tumors by convection delivery. The administration of ganciclovir was continued for another 8 days. The result of the therapy was a reduction in the size of tumors and a significant increase in the survival rate of animals compared to glioma-untreated rats and other control groups who were injected with nanoparticles, DNA and ganciclovir in different combinations.

Fig. 3. Glioma cell lines treated with a new approach. Leftward: by itself, ganciclovir has no effect on glioma cells. Right: Exposure to ganciclovir in combination with HSVtk gene-coding nanoparticles leads to glioma cell death.

The authors believe that the approach they have developed can be used by doctors during surgical removal of glioma, traditionally used to treat this disease. In the future, they plan to test the ability of nanoparticles to deliver other therapeutic genes and capabilities to malignant cells, as well as their effectiveness with systemic administration, which will allow them to be used not only in the therapy of a wide range of solid tumors, but also in the treatment of systemic malignant diseases.

Article by Antonella Mangraviti et al. Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survivalin Vivo is published in the journal ACS Nano.

Evgeniya Ryabtseva

Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the National Institute of Biomedical Imaging and Bioengineering:
Gene Therapy Advance Thwarts Brain Cancer in Rats.