English
Abstract
Metastasis is the main cause of failure in anticancer therapies, and is frequently related to poor prognosis for patients. The true challenge in extending cancer patient life expectancy, eventually managing cancer as a chronic disease with periodic but controllable relapses, relies on the development of effective therapeutic strategies specifically targeting key mechanisms involved in the metastatic cascade. Traditional chemotherapy with alkylating agents, microtubule inhibitors, and antimetabolites has shown limited efficacy against metastatic cells, largely due to the emergence of chemoresistant populations that undergo epithelial-to-mesenchymal transition (EMT), promoting the colonization of distant organs and sustaining metastatic progression. This scenario has spurred significant efforts to identify small molecules and biologics capable of interfering with specific steps in the metastatic process. In this review, we provide an overview of recent advances involving small interfering RNAs (siRNAs) and microRNAs (miRNAs) in cancer therapy. Although most of these agents are still under investigation and have not yet been approved for clinical use, insights into their development stage offer valuable information to identify new targets in the ongoing fight against metastasis. Particular emphasis is placed on the role of chemical modifications applied to siRNAs, such as backbone, sugar, terminal, base, and conjugation changes, and how these factors influence their stability, immunogenicity, and targeting precision. By integrating these aspects into the discussion, this review provides a focused and up-to-date resource for researchers in medicinal chemistry, drug delivery, and pharmaceutical formulation, where molecular design plays a critical role in therapeutic success.
Keywords:
miRNA; siRNA; anticancer therapy; molecular design; targeted delivery
1. Introduction
mRNA technology, together with innovative drug delivery solutions, has opened new pathways in pharmacological research; mRNA’s role in vaccine design, targeting either viral or tumor antigens, is continually gaining prominence. Alongside these trends, the possibility of modulating gene expression from within the cell, by regulating RNA translation and editing, has always attracted scientists from various fields, including clinical research. The finding that mRNA expression can be modulated by micro RNAs (miRNAs), with profound implications on post-transcriptional regulation and eventually gene expression, suggested the idea that this way of modulating gene and oncogene expression could be exploited as a therapeutic strategy. This strategy can be considered the opposite side of the therapeutic design aimed at blocking proteins, e.g., receptors or enzymes, by using chemical or biological agents: in this latter case, in fact, the gene product, after translation and post-translational modifications, is inhibited in its cellular functions by small molecules or antibodies. The discovery of miRNAs suggested that the target protein could be inhibited by selectively blocking its synthesis using synthetic, targeted RNAs named short interfering RNAs (siRNAs) or by directly targeting miRNAs, making other agents virtually unnecessary, with evident advantages under the side effect profile.
The functions of miRNAs, indeed, appear to be complex; miRNAs bind to target mRNAs, generating a double-strand RNA that cannot undergo the following translation process, eventually resulting in the degradation or inhibition of the target mRNA. The functions of miRNAs are complex, since a single miRNA can bind to and regulate a wide range of mRNAs, and entire cellular pathways can be modulated by a specific miRNA. This modulation can lead to relevant biological outcomes and deeply influence the cell’s fate. For this reason, miRNAs immediately appeared to be a potential pharmacological tool, and the importance of these fine intracellular regulators was recognized by the awarding of the 2024 Nobel Prize in Physiology or Medicine to Victor Ambros and Gary Ruvkun, who first identified and described them.
The article is reprinted from MDPI, original link:https://www.mdpi.com/1422-0067/26/17/8703
The FAI climbed 5.9 percent year-on-year in the first 11 months of 2018, quickening from the 5.7-percent growth in Jan-Oct, the National Bureau of Statistics (NBS) said Friday in an online statement.
The key indicator of investment, dubbed a major growth driver, hit the bottom in August and has since started to rebound steadily.
In the face of emerging economic challenges home and abroad, China has stepped up efforts to stabilize investment, in particular rolling out measures to motivate private investors and channel funds into infrastructure.
Friday's data showed private investment, accounting for more than 60 percent of the total FAI, expanded by a brisk 8.7 percent.
NBS spokesperson Mao Shengyong said funds into weak economic links registered rapid increases as investment in environmental protection and agriculture jumped 42 percent and 12.5 percent respectively, much faster than the average.
In breakdown, investment in high-tech and equipment manufacturing remained vigorous with 16.1-percent and 11.6-percent increases respectively in the first 11 months. Infrastructure investment gained 3.7 percent, staying flat. Investment in property development rose 9.7 percent, also unchanged.