Abstract
Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD) and particularly small interfering RNAs (siRNAs), are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC), a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work.
Highlights
Antisense oligonucleotides, triplex forming-oligo-nucleotides, ribozymes, DNAzymes, antisense oligonucleotides, aptamers, long non-coding RNAs, small interfering RNAs (siRNAs) and miRNAs belong to an attractive class of molecules collectively named nucleic acid-based drugs (NABDs) [1,2,3,4,5,6]
Despite the great therapeutic potential of siRNAs, their practical use is limited by the chemical nature that does not allow the administration in the naked form
We reported that eEF1A2 is overexpressed in human hepatocellular carcinoma (HCC) cell lines and that its overexpression correlates with cancer cell growth and differentiation phenotype [97]. eEF1A2 overexpression has been detected in HCC human tumor specimens [98,99]
Summary
Triplex forming-oligo-nucleotides, ribozymes, DNAzymes, antisense oligonucleotides, aptamers, long non-coding RNAs, siRNAs and miRNAs belong to an attractive class of molecules collectively named nucleic acid-based drugs (NABDs) [1,2,3,4,5,6]. Among NABDs, siRNAs (small interfering RNA) are the molecules mostly investigated as potential therapeutics In this regard, many hopes are placed on siRNAs to combat the second cause of death in the industrialize Countries, i.e., tumors. SiRNA siRNAs are short double-stranded RNA molecules approximately 22 nucleotides long They can be of intracellular (endo-siRNA) or exogenous origin, being in this last case generated from invasive nucleic acids such as viruses and transposons [23] or introduced for research purposes. With regard to their mechanism of action (Figure 1), of the two filaments forming siRNAs, one (antisense strand) is up-taken by a cellular protein complex termed RISC (RNA-induced silencing complex), while the other (sense strand) is not up-taken by RISC and is discarded. This results in the RISC-mediated degradation of the target RNA with the consequent down-regulation of gene expression. siRNA can be chemically generated and effectively used to target gene mRNA causing disease as shown by many works [3,24,25,26,27,28,29]
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