Methods of miRNA delivery and possibilities of their application in neuro-oncology

Abstract

In the current phase of medical progress, practical neuro-oncology faces critical challenges. These include the quest for and development of innovative methodological approaches, as well as the enhancement of conventional therapies to boost their efficacy in treating brain tumors, especially the malignant varieties. Recent strides in molecular and cellular biology, molecular genetics, and immunology have charted the primary research pathways in the development of new anti-cancer medications, with a particular focus on microRNA (miRNA)-based therapy. MiRNAs possess the ability to function as suppressors of tumor growth while also having the potential to act as oncogenes. MiRNAs wield control over numerous processes within the human body, encompassing tumor growth, proliferation, invasion, metastasis, apoptosis, angiogenesis, and immune responses. A significant impediment to enhancing the efficacy of brain tumor treatment lies in the unresolved challenge of traversing the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to deliver therapeutic agents directly to the tumor tissue. Presently, there is a worldwide effort to conduct intricate research and design endeavors aimed at creating miRNA-based dosage forms and delivery systems that can effectively target various structures within the central nervous system (CNS). MiRNA-based therapy stands out as one of the most promising domains in neuro-oncology. Hence, the development of efficient and safe methods for delivering miRNA agents to the specific target cells within brain tumors is of paramount importance. In this study, we will delve into recent findings regarding various methods for delivering miRNA agents to brain tumor cells. We will explore the advantages and disadvantages of different delivery systems and consider some clinical aspects of miRNA-based therapy for brain tumors.

Keywords: Blood-brain barrier; Brain tumors; Delivery system; Therapy; Vectors; miRNA.

Fig. 1

Schematic illustration of the blood-brain barrier (BBB). The existence of the BBB is a necessary and most important condition for the normal functioning of the central nervous system (CNS).

Fig. 2

Comparative characteristics of the structure of the blood-brain barrier (BBB) in normal and blood–tumor barrier (BTB) is in brain tumors. BTB is generally considered « leakier » than BBB. BTB is characterized by an aberrant distribution of pericytes, and loss of astrocyte end foots and neuronal connections. T cell subpopulations and peripheral monocytes are found in brain tumors, indicating permeability to circulating immune cells. In addition, junctional proteins are reduced in endothelial cells (ECs) of BTB, and the intratumoral vasculature never fully restores normal BBB in brain metastases. Although BTB is "defective", it retains important aspects of the BBB, including the expression of active efflux transporters in ECs and tumor cells.

Fig. 3

Schematic illustration of major biological barriers to drugs in the treatment of brain tumors. It has been shown that with the help of various modifications, as a vector delivery system, it is possible to overcome biological tumor barriers with the effective use of antitumor agents, including microRNAs (miRNAs) agents.

Fig. 4

Strategies to overcome problems with the efficiency, specificity, and safety of delivering miRNA agents to the body to inhibit oncogenes or activate oncosuppressor genes. The efficiency of the interaction of exogenous microRNAs (miRNAs) (mimics or antagomiRs) with endogenous (tumor) microRNAs and mRNA targets can be increased by increasing the bioavailability for target loci. Approaches to improve efficiency: 1) prevention of enzymatic degradation through stable encapsulation; 2) immunity evasion due to biocompatible coating and self-antigens; 3) increased extravasation due to ligands that induce transcytosis of the vascular endothelium; and 4) enhancement of intracellular and nuclear penetration of miRNAs through cationic polymers. Specificity can be improved by decorating the delivery vehicle with target ligands and designing delivery vehicles that respond to external or tissue-specific signals. Approaches to improve safety: 1) implementation of mechanisms of local retention or systemic inhibition; and 2) the use of biocompatible materials to minimize local inflammation.

Fig. 5

Viral delivery systems for microRNA (miRNA) agents. Various types of viral vectors are considered, such as retroviral, adeno-associated, and lentiviral vector systems, vector systems based on adenoviruses, and herpes simplex virus type 1.

Fig. 6

Non-viral delivery systems for microRNA (miRNA) agents. Non-viral vectors are represented by organic, synthetic, and inorganic compounds.