Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances - PubMed (original) (raw)

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Nanocarrier mediated delivery of siRNA/miRNA in combination with chemotherapeutic agents for cancer therapy: current progress and advances

Nishant S Gandhi et al. J Control Release. 2014.

Abstract

Chemotherapeutic agents have certain limitations when it comes to treating cancer, the most important being severe side effects along with multidrug resistance developed against them. Tumor cells exhibit drug resistance due to activation of various cellular level processes viz. activation of drug efflux pumps, anti-apoptotic defense mechanisms, etc. Currently, RNA interference (RNAi) based therapeutic approaches are under vibrant scrutinization to seek cancer cure. Especially small interfering RNA (siRNA) and micro RNA (miRNA), are able to knock down the carcinogenic genes by targeting the mRNA expression, which underlies the uniqueness of this therapeutic approach. Recent research focus in the regime of cancer therapy involves the engagement of targeted delivery of siRNA/miRNA in combinations with other therapeutic agents (such as gene, DNA or chemotherapeutic drug) for targeting permeability glycoprotein (P-gp), multidrug resistant protein 1 (MRP-1), B-cell lymphoma (BCL-2) and other targets that are mainly responsible for resistance in cancer therapy. RNAi-chemotherapeutic drug combinations have also been found to be effective against different molecular targets as well and can increase the sensitization of cancer cells to therapy several folds. However, due to stability issues associated with siRNA/miRNA suitable protective carrier is needed and nanotechnology based approaches have been widely explored to overcome these drawbacks. Furthermore, it has been univocally advocated that the co-delivery of siRNA/miRNA with other chemodrugs significantly enhances their capability to overcome cancer resistance compared to naked counterparts. The objective of this article is to review recent nanocarrier based approaches adopted for the delivery of siRNA/miRNA combinations with other anticancer agents (siRNA/miRNA/pDNA/chemodrugs) to treat cancer.

Keywords: Cancer; Clinical trial; Combination therapy; Nanotechnology; miRNA; siRNA.

Copyright © 2014 Elsevier B.V. All rights reserved.

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Figures

Figure 1

Figure 1

RNA interference mechanism: siRNA – The siRNA pathway begins with cleavage of dsRNA by enzyme DICER resulting in siRNA in the cytoplasm of cell [34, 49]. The siRNA then binds to Argonaute (AGO2) protein and RNA inducing silencing complex (RISC)[37]. One strand of the siRNA duplex (the passenger strand) is removed by AGO2 resulting in RISC containing guide strand [50]. The activated RISC-siRNA binds to the complementary sequences on the mRNA and results in its cleavage and degradation [51]. Biogenesis of miRNA – The RNA polymerase II or III are responsible for the production of primary-miRNA’s (pri-miRNA) [36, 52]. In the nucleus, the resulting pri-miRNA’s are cleaved by the microprocessor complex Drosha [53]. The pre-miRNA is transported to the cytoplasm by Exportin 5(XPO5) and the loop structure is removed by the Dicer complex (Dicer – TAR binding protein) resulting in miRNA or miRNA duplexes [54, 55]. One strand of the duplex is incorporated into AGO2 and RISC which targets mRNA and results in its degradation[56]. (Adapted with permission from ref.[57]).

Figure 2

Figure 2

Mechanism of sensitization of resistant cancer cells by co-delivering siRNA and a chemotherapeutic agent. Therapeutic agents encapsulated in nanoparticles evade the efflux pump via endosomal internalization. Once in the endosome, the specifically designed nanoparticles releases siRNA/miRNA and drug in the cytosol resulting in the cytotoxic effect.

Figure 3

Figure 3

Schematic representation of non-targeted and targeted LCP nanoparticles adapted with permission from ref. [48].

Figure 4

Figure 4. Schematic illustration of the formation of mixed micellar system using G (4)-PAMAM-D-PEG-DOPE/PEG-DOPE mixed micellar system

A poly (ethylene glycol) – dioleoylphosphatidyl ethanolamine (PEG-DOPE) modified G (4)-PAMAM nanocarrier used to deliver siRNA targeting green fluorescence protein. (Adapted with permission from ref. [138])

Figure 5

Figure 5

Schematic representation of self-assembled cationic micelles of PDMAEMA–PCL– PDMAEMA triblock copolymers for the simultaneous combinatorial delivery of PTX and siRNA. The figure depicts the release of siRNA from the cationic micelles inside the cell and degradation of mRNA resulting in its action.

Figure 6

Figure 6

Schematic representation of cationic solid lipid nanoparticles complexed with siRNA A) Empty solid lipid nanoparticles B) PTX loaded solid lipid nanoparticles (adapted with permission from ref. [147])

Figure 7

Figure 7

Schematic illustration of the formation of multifunctional nanoassemblies comprising of DOX and siRNA. (Adapted with permission from ref.[208].

Figure 8

Figure 8

A Schematic illustration of the formation of micellar nanoparticles. (Adapted with permission from ref. [148])

Figure 9

Figure 9

Lipid Nanoparticle for systemic delivery (Adapted from online alnylam pharmaceuticals)

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