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Review
. 2018 Mar 28;23(4):777.
doi: 10.3390/molecules23040777.

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

Rossella Farra  1 , Francesco Musiani  2 , Francesca Perrone  3 , Maja Čemažar  4   5 , Urška Kamenšek  6 , Federica Tonon  7 , Michela Abrami  8 , Aleš Ručigaj  9 , Mario Grassi  10 , Gabriele Pozzato  11 , Deborah Bonazza  12 , Fabrizio Zanconati  13 , Giancarlo Forte  14 , Maguie El Boustani  15   16 , Lucia Scarabel  17 , Marica Garziera  18 , Concetta Russo Spena  19   20 , Lucia De Stefano  21   22 , Barbara Salis  23   24 , Giuseppe Toffoli  25 , Flavio Rizzolio  26   27 , Gabriele Grassi  28   29 , Barbara Dapas  30
Affiliations
Review

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

Rossella Farra et al. Molecules. .

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.

Keywords: HCC; optimized drug delivery; siRNA.

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Conflict of interest statement

The authors declare no conflict of interest. “The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results”.

Figures

Figure 1
Figure 1
siRNA mechanism of action. The antisense strand of the siRNA is up-loaded by the catalytic protein complex RISC (RNA-induced silencing complex), while the sense strand is discarded. The antisense strand drives RISC to a target complementary mRNA, resulting in the specific RISC-mediated cleavage and subsequent degradation by cellular RNAses.
Figure 2
Figure 2
Biological barriers to siRNA delivery. For systemically released siRNAs the first obstacle is represented by blood nucleases, which can induce their degradation. The siRNAs have then problem to cross the vessel wall (extravasation) then the ECM (Extra Cellular Matrix) and finally the cell membrane. Once into the cell, siRNAs have to evade from endosome.
Figure 3
Figure 3
Polymers employed as siRNA delivery materials: chemical structures.
Figure 4
Figure 4
Specific aspects related to an optimized siRNA delivery to HCC.
Figure 5
Figure 5
Temporary evolution of the % of target protein (solid line) and the % of cells number (dashed line) according to the Bartlett & Davis model (model parameters are those reported in Bartlett & Davis [107]).
Figure 6
Figure 6
(A) Schematic representation of the polymer from ref. [113]; PHEA: α,β-poly-(N-2-hydroxyethyl)-d,l-aspartamide, DETA: diethylene triamine, PEG: polyethylene glycol, GAL galactose, siRNA: small interfering RNA, ASGP-R: Asialoglycoprotein receptor; (B) Schematic representation of the polymer from ref. [114]. GTC: galactose modified trimethyl chitosan-cysteine, TPP: sodium tripolyphosphate, γ-PGA: γ-polyglutamic acid; on the left are shown the single components, on the right the assembled particle.
See this image and copyright information in PMC

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