Polymer-Mediated Delivery of siRNAs to Hepatocellular Carcinoma: Variables Affecting Specificity and Effectiveness

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.

5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway

“…Thus, the reduced angiogenesis in larvae injected with JHH-6 can be attributed to the reduced growth of JHH-6 due to 5-Aza. This observation is of particular importance considering that HCC is a highly vascularized tumor [ 71 ], and therefore, anti-angiogenic molecules are of potential benefit.…”

“…Although these data are very promising, they need to be implemented with the evaluation of the effects of the systemic administration of 5-Aza (in progress). In this context, we believe [ 71 , 72 ] that trans-arterial tumor delivery would be the most appropriate route, possibly in combination with targeted delivery of 5-Aza, as we have recently developed for anti-HCC siRNAs [ 44 ].…”

<p>Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach</p>

“…Several polymeric nanoparticles have been approved as drug carriers for human use 104. Due to their excellent properties, a variety of polymers including cationic polymers such as polyethylenimine (PEI), polysaccharides such as cyclodextrin (CD) and chitosan have been studied for siRNA delivery 105,106. As a general rule, polymer nanoparticles exhibit positively charged units to facilitate electrostatic binding of siRNA; however, the use of covalent strategies involving siRNA and polymers have been frequently prepared by using degradable linkers such as disulfide or thiol-maleimide bonds 107…”

Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma

“…The selectivity of the cell membrane hinders the internalization of the sequences introduced; thereafter, the endosome poses a great threat to the integrity of the sequences, as they could be degraded by endosomal enzymes. Moreover, in a complex in vivo system, the obstacles are exacerbated due to the complexity of the human body [ 144 ]. Great progress has been made during the past decade regarding the delivery of RNAi.…”