An Overview of Oncolytic Virus Therapy (Part Two)

1. Bionic mineralization of oncolytic viruses
There are many types of calcium materials. The most studied ones include calcium phosphate, calcium carbonate, calcium silicate and calcium fluoride. When they enter the body, they can be dissolved into non-toxic ions, so as to participate in and maintain the normal metabolism of the body. Based on its good biocompatibility and biodegradability, it has been widely used in various fields of biomedicine. Biomineralization refers to the conversion of ions in solution into solid phase minerals through the participation of biological macromolecules (cells, viruses, organic substrates) in the regulation and control process. Biomineralization is not only a way of preparing biological materials, but also a biological strategy formed during natural evolution. In nature, many organisms improve their ability to resist the external environment through biomineralization, such as diatoms, mollusks, and some plants. Some eggs can be stored in the external environment for a long period of time because they contain a mineralized shell. Teeth, pearls, shells, etc. also have a natural mineralized layer to protect the internal structure and stability. Inspired by biomineralization in nature, relevant researchers use the negatively charged amino acids on viral proteins to electrostatically adsorb divalent calcium ions, and form a calcium mineralization layer on the virus surface through the co-precipitation between calcium ions and phosphate to protect the virus. The surface protein makes its structure independent of temperature and electrolyte changes. When injected into the tumor-bearing mice through the tail vein, it can significantly reduce liver toxicity, while evading the body's immune response. When it reaches the tumor site, the tumor has a slightly acidic environment. It will dissolve the mineralized layer on the surface of the virus to release the virus and make it play the role of tumor killing. On this basis, HUANG et al. innovatively constructed a functional oncolytic adenovirus composite nano-system (OA@MnCaCs) coated with an artificial shell of calcium carbonate/manganese, the oncolytic virus drug platform can protect the virus evade the body's immune monitoring effect, and efficiently concentrate in the tumor site. When it reaches the slightly acidic environment around the tumor, the calcium carbonate/manganese shell will dissolve, releasing Ca+ and Mn2*, destroying the appropriate tumor acidic environment for tumor growth; the released Mn2+ can achieve better magnetic resonance imaging (MRI) function. It can also decompose H and O2 in tumor tissue to produce oxygen, improve hypoxia in the tumor microenvironment to enhance the replication ability of the virus; the oxygen produced will also increase the concentration of HbO in the tumor tissue and obtain a better photoacoustic imaging effect. Therefore, the new oncolytic virus drug platform plays an important role in the live tracking of tumor-bearing mice and anti-tumor.
2. Oncolytic virus and organic framework material
Organic frame materials have attracted more and more attention due to their large specific surface area, good thermodynamic stability, plasticity, and special optics. The organic framework materials currently under research mainly include covalent organic frame-work (COF), metal-organic frame-work (MOF) and nanocoordi-nation polymer (NCP). As a synthetic coordination polymer with high specific surface area and porous crystallinity, MOF has been widely used in proteins, oligonucleotides, and even more complex structures, such as viruses, bacteria, and eukaryotic cells. Research by LIANG et al. proves that organic substances such as proteins and nucleic acids can promote self-crystallization by enriching the skeleton of biological macromolecules, thereby rapidly inducing the formation of a metal-organic framework protective layer under physiological conditions. LI et al. used tobacco mosaic virus (TMV) as a biological template, and successfully constructed TMV@ZIF-8 composite particles with a core-shell crystal or large crystal structure. ZIF-8 has been proven to be a robust MOF material that encapsulates and protects biological substances. This material can effectively protect TMV from environmental stresses of external heat and proteases. A study coated ZIIF-8 on the surface of TMV. Immuno and spectroscopic analysis confirmed that after MOF material was coated, the thermal and chemical stability of the virus were significantly enhanced, and the animal model was further clarified after coating ZIF-8 Virus biological safety, integrity and original immunogenicity.
Combination therapy
Due to the heterogeneity of the tumor and the complexity of the tumor microenvironment, even if the viral vector is used to block the immunogenicity of the virus, the tumor treatment effect is still not ideal. Therefore, many researchers combine oncolytic viruses with other tumor treatments to achieve the goal of synergistic tumor suppression.
1. Oncolytic virus combined chemotherapy
A large number of studies have shown that some oncolytic viruses can cooperate with specific chemotherapeutic drugs and can play a better therapeutic effect in animal tumor models. This synergistic effect can reduce the potential complications of oncolytic viruses. It does not affect the overall efficacy. In addition, it can reduce the dosage of the drug or shorten the course of treatment under the same conditions, thereby reducing the side effects that the drug may bring to the body, and also reducing the probability of the body developing resistance. As an effective immunosuppressant, cyclophosphamide plays an important role in the treatment of leukemia and various solid tumors. Cyclophosphamide is the first chemotherapy drug used in combination with oncolytic viruses. With the development of more targeted drugs, the use of new, less toxic drugs in combination with oncolytic viruses to improve the tumor killing effect has good clinical application prospects. JIN et al. used recombinant adenovirus ATV expressing specific apoptotic proteins in combination with cisplatin to treat A549 tumor-bearing mice, which can reduce the toxicity of ATV and cisplatin, while inhibiting the growth of transplanted tumors and prolonging the survival of tumor-bearing mice. The study showed a synergistic effect, and the study laid the foundation for subsequent preclinical studies.
Gemcitabine is used in the treatment of pancreatic cancer-line chemotherapy drugs. MAY et al. found that only a small amount of oncolytic measles virus combined with initial concentration of gemcitabine in vitro can reduce the number of pancreatic cancer cells by more than half. This method is a potential new method for the treatment of advanced pancreatic cancer. Although oncolytic virus combined with chemotherapy shows a good synergistic effect on the treatment of tumors, whether the two can play a good synergistic effect depends on the tumor type, virus strain and the types of chemotherapy drugs used, etc.
2. Oncolytic virus combined radiotherapy
Radiotherapy can promote the activation of certain signaling pathways of tumor cells or increase the replication of oncolytic viruses by up-regulating the expression of key genes, and the expression of related genes can also further increase the tumor killing effect map of radiotherapy. BIELER et al. found through research that radiotherapy can promote the nuclear localization of human transcription factor YB-1, thereby increasing the replication and release capacity of oncolytic adenovirus. This strategy significantly inhibited the the growth of the subcutaneous astroglioma cells U373 tumor-bearing mice.
3. Oncolytic virus combined immunotherapy
Because some immunosuppressive signal receptors are overexpressed in tumor cells, and the tumor microenvironment will inhibit the activity of immune cells at the tumor site. Therefore, there are very few immune cells that can function around tumor cells. Oncolytic viruses will stimulate the body's immune response after entering the tumor site, transforming the "cold" tumor microenvironment with few immune cells into the "hot" tumor microenvironment with more immune cells and cytokine infiltration.
To be continued in Part Three…

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