APPROACH

One promising direction in cancer treatment is the development of gene therapy based on antisense oligonucleotides. This approach, mainly using complementary polynucleotides to inactivate genes, holds great promise in the fight against cancer. However, cancer gene therapy faces significant challenges: the destruction of synthetic complementary nucleotides by blood nucleases, limited penetration into cells, and sensitivity to cell genome repair systems. These hurdles require immediate attention and further research. According to the principles of Systems Evolution, all man-made systems are progressing towards miniaturization. What was once large is now microscopic – from a considerable radio lamp to a microprocessor and from robots to nanorobots. These nanorobots are designed to mimic the adaptive capabilities of living organisms, responding to environmental conditions within the body. Specifically, our technology draws inspiration from viral behavior – the self-assembly of proteins and polynucleotides into complex virions. We aim to develop a new class of adaptive, multi-functional drug delivery systems by applying this principle to therapeutic nanostructures.

While one molecule can perform a single function, complex nanostructures based on modified RNA and peptides can carry out multiple sequential operations. They can also self-organize and self-assemble into more intricate and hybrid structures with entirely different properties than the original components. This behavior resembles viruses, which self-assemble from a mix of proteins and polynucleotides into complex virions. Our developed nanorobots are supramolecular structures based on peptides or quasi-living nanostructures. Living organisms can adapt to their surroundings. We have proposed structures based on antisense-oligoRNA, which can self-assemble on cellular RNA (such as tRNA, mRNA, and rRNA) and inhibit their functions. Different approaches are taken to designing antisense oligonucleotides. However, the principle of their interaction with targets remains the same: the formation of hydrogen bonds between complementary nucleotides with increased resistance to nucleases. It’s important to note that the principle of gene inactivation through their complementary interaction with antisense nucleotides remains consistent – the formation of hydrogen bonds. These are also known as complementary miRNAs, which selectively block the synthesis of specific proteins in the cell. It is well known that many adenocarcinomas capture oligonucleotides and nanoparticles through pinocytosis, while healthy cells cannot capture small oligonucleotides and liposomes. This ensures selective accumulation of the proposed protected oligonucleotides (antisense oligoRNA – MoLRx) in cancer cells and the absence of toxicity of the MoLRx composition. To obtain MoLRx, we used antisense oligomeric fragments of RNA – recognized by ribosomes. This antisense oligo-RNA gave the property of complementarity and protection against nucleases by simultaneous combinatorial acylation without subsequent separation of the combinatorial library into individual compounds. Selective accumulation of the MoLRx in the cancer cell leads to cancer cell hybridization with complementary targets in the cancer cell’s tRNAs, mRNAs, and rRNAs (Figure 1). This results in a gradual halt in protein synthesis due to the blockade of protein synthesis in incorporating amino acids into the polypeptide chain. The action of MoLRx is based on the induction of apoptosis through the termination of protein synthesis. We designed antisense oligo RNAs (MoLRx), consisting of thousands of fragments of different sizes (up to 30 nucleotides) and sequences, which act similarly to polychemotherapy. After carboxylation, these MoLRx exhibited the desired antisense properties and could offer some benefits of polychemotherapy. Our research on MoLRx aims to overcome multidrug resistance, potentially extending patient survival and reducing mortality associated with MDR cancers. The oligomeric fragments of RNA contain numerous adenine and guanine groups that can be modified. A wide variety of derivatives with different lengths and charges are created through combinatorial synthesis. Each component in this mixture pairs with a specific region in one of the t-RNAs, m-RNAs, and r-RNAs (multitarget drugs). This redundancy helps prevent the development of cancer cells resistant to multiple chemotherapy treatments. Modifications that resist nucleases also enable the fragments to remain in cancer cells and the bloodstream longer.

Team Expertise: Our team uniquely integrates the Theory of Inventive Problem Solving (TRIZ) into pharmaceutical development and includes Ph.D. holders with diverse educational and practical backgrounds. We are composed of experts in pharmacology, microbiology, and drug design and have recently secured 10 new US patents in drug design, including three in MDR, bringing our total to over 220 granted patents, with several industry-implemented innovations. Our principal investigator and consultant are the authors of the proposal’s granted patent and a peer-reviewed published article. Key personnel include a clinician experienced in anticancer trials and multicenter studies. Our diverse expertise and systems approach position us to tackle complex challenges effectively.