Laboratory for Theranostics in Urologic Oncology

Scientific results:

On the basis of genetic and proteomic analysis methods, we have developed a method of microprecipitation reaction (MPR) typing with the isolation of six main groups (the BOLD classification), each of which has its own expressed molecular and histological features and requires a different approach when compiling therapy recommendations. It is important that such differentiation was reproducible for both non-muscle-invasive and muscle-invasive MPR, as well as demonstrated a good correlation with the used classifications. Apart from new approaches to low-invasive MPR diagnostics, there are extremely relevant problems of the development of a unique pharmacological preparation capable of, either in the form of a monotherapy or in combination with other medications, suppress the invasion and metastasis of urogenital carcinomas, as well as innovative means of its targeted delivery. Within the project we have developed a pharmaceutical composition capable of forming hydrogels in vivo – in bladder muscle tissue – with encapsulated medications ensuring the suppression of invasion and metastasis of bladder carcinoma in the case of monotherapy with additional cytostatic effect in the case of combined use with other medications. The medical preparations eluted from hydrogel implanted into bladder muscle tissue in the process of resorption of the gel are able to suppress the invasion and metastasis of bladder cancer in the case of monotherapy, with additional cytostatic effect in the case of combined use with other preparations. Hydrogel forms right after the removal of bladder cancer neoplasms by injection via a catheter. The prolonged period of the action of hydrogel is three months.  It is worth noting that the proposed hydrogel system can be used not only in bladder cancer therapy but also, for instance, in pleural, pericardial and, possibly, abdominal cavity mesotheliomas.

We have developed a method of the synthesis of epithelial-mesenchymal transition (EMT) inhibitors, studied their influence on the mechanical and biological characteristics of cells as well as researched the influence of substrate hardness on the phenotype of the cells.

To minimize the use of invasive biopsy procedures, we have proposed and developed a method of so-called liquid biopsy, in which tumor cells are extracted from biological fluids using specially designed chips based on dimethyl polysiloxane (silicone). Protocols have been developed for the extraction of tumor cells from blood, urine and sperm of patients with oncological diseases of the genitourinary system, and in doing so we conducted a molecular immunological typing of extracted cells according to their markers expressed on the surface of the cells. In particular, we have found that the liquid biopsy of seminal fluid allows to  implement non-invasive prostate cancer diagnostics with absolute specificity and sensitivity, as it has been demonstrated in a group of over 50 patients with a diagnosed illness. A project aimed at the commercialization of this development received support from the Rosatom State Atomiс Energy Corporation.

The brewing crisis in nanomedicine, whose emergence promised a revolution in oncological diagnostics and therapy, is explained by the extreme complexity of cancer biology. The effect of increased permeability and retention of encapsulated oncological drugs became the basis of nanomedicine, but did not allow to implement the efficient delivery of medications to therapeutic targets – cancer cells – while minimizing side effects. In our project we have successfully implemented an alternative concept of the delivery of anti-tumor drugs based on new nanomaterials capable of accumulating in the vessels of the target tumor or a metastasized organ with the subsequent fast release of the encapsulated medication and penetration into the target tissue [Parakhonskiy et al. Adv. Mater. Today 2021]. This approach to pharmaceutical delivery had been predicted by theoretical modeling and confirmed experimentally with the use of the rationally designed metal-organic frameworks MIL-101 (Fe). MIL-101 nanoparticles loaded with doxorubicin are quickly captured by the lung vasculature, degrades in blood vessels over 15 minutes and releases the pharmaceutical that quickly permeates the organ. Using animal models of early and late stages of metastasis of the B16-F1 melanoma, we have demonstrated a significant improvement of the results of treatment with a mitigation of lung melanoma nodes, by the factor of 11 and 4,3 respectively [Zelepukin et al., Nat. Comm., in press]. To implement a theranostic approach, we have synthesized multi-layered polyelectrolyte capsules based on the sulfate dextran/poly-L-arginine complex that contain a substituted phthalocyanine complex (zinc phthalocyanine, trademark name Holosens). It has been demonstrated that Holosens-containing capsules can be visualized with certainty inside cells, also demonstrating a high phototoxicity, which allows to realize the therapeutic photodynamic modality of such capsules with the use of 2D and 3D cell models. A fluorescence bioimaging system has been created for in vivo visualization. The device features a unique combination of high sensitivity, speed and flexibility  in optical luminescence imaging of small laboratory animals in vivo. We have proposed the use of inhibitors of epithelial-mesenchymal transition (EMT) that occurs during the progression of metastasis of tumors.

Implementation of research results :

The non-invasive diagnostics of prostate cancer with absolute specificity and sensitivity, as it has been demonstrated in a group of over 50 patients with a diagnosed disease, has been implemented on the basis of seminal fluid biopsy with the use of an inertial microfluid device. A project for the commercialization of this technology has been supported by Rosatom State Atomiс Energy Corporation. We have also developed and studied a  high-performance microfluidic chip  that allows to enrich bladder cancer cells isolated from urine.

We have synthesized several compounds that demonstrate efficient inhibition of the transformation growth factor (TGF-beta), including the pharmaceuticals А83-01, А77-01 as well as the new compound. We have developed a pharmaceutical compound capable of forming hydrogels directly in bladder muscle tissue with the encapsulated drug А83-01. The hydrogel is formed immediately after the removal of bladder cancer tumor by injection via a catheter. The prolonged action of hydrogel lasts three months. It has been found that the concentration in of the drug bladder tissue is 3000 times higher than in the case of its oral administration. The performed research leads to the creation of a drug for bladder cancer treatment. The developed drug is original, does not have counterparts in the world and demonstrates promising results for the planned pre-clinical testing and the transition to clinical testing.

We have created a specialized photoluminescence imaging system for the visualization of small animals in vivo. The device ensures a unique combination of a high sensitivity, speed and flexibility when performing the optical photoluminescence imaging of small laboratory animals in vivo. The creators of the device have experience of commercial sales of the system.

The Laboratory has synthesized polymer nanoparticles that are colloid-stable in saline solutions with a size of 200 nm loaded with a chemotherapy drug and a fluorescent coloring agent. The produced polymer nanoparticles have been successfully modified with a HER2-detecting protein while preserving the stability of nanoparticles. 

Education and retraining of personnel:

• One employee of the Laboratory has completed an internship at the leading scientist’s place of work.
• New education courses have been created: «Nanotechnology and medicine» and «Microfluidics in biology and medicine» (launched in  September 2021).
• One Doctor of Sciences dissertation and two Candidate of Sciences dissertations have been prepared and defended. 

Organizational and infrastructural transformations:

Employees of other divisions of Sechenov University use the equipment of the Laboratory to conduct research in the domain of regenerative medicine, diagnostic oncology and in vivo imaging. 

Other results:

The Laboratory has independently created unique devices:

• a device based on the principle of inertial separation of cells from fluids with the use of  microfluidic technologies for the study of the possibility of early diagnostics, monitoring of the therapeutic response as well as high-precision profiling of circulating cancer cells.  The created devices, technologies and methodologies can become an alternative to tissue biology;
• a device allowing to test biomimetic models of viruses synthesized at the Laboratory on the basis of fluorescent polymer nanoparticles.  The created device allows to assess the propagation of viruses, including in aerosols.

Collaborations:

• Nizhniy Novgorod State University, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Federal Scientific Research Center «Crystallography and Photonics» of the Russian Academy of Sciences, Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, National University of Science and Technology «MISIS», Skolkovo Institute of Science and Technology (Russia), University of Technology Sydney, Macquarie University (Australia), Guangzhou Institute of Biomedicine and Health (China PR), Queen Mary University of London (United Kingdom), Matter and Complex Systems, CNRS, University of Paris (France): hoint research and publications.

• Institute of Urology and Human Reproductive Health of the I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation: clinical research, training of members of the academic staff in the postgraduate school.