**1. Introduction**

Noncoding RNAs have many functions such as gene silencing, DNA imprinting, and demethylation. An increased number of noncoding RNAs have been discovered in gene regulation and RNA processing. Of these, small interfering ribonucleic acid (siRNA) and microRNAs (miRNAs) that can interfere with the translation of the target mRNA transcript are small ncRNAs that are the cleavage products of the dsRNA. MicroRNAs are a class of endogenous RNA that results in mRNA translation inhibition or degradation, which regulates cell differentiation, proliferation, and survival, while synthetic siRNA can initiate the silencing of target genes without interrupting natural mRNA pathways.

siRNA is a promising therapeutic solution preventing gene overexpression in various pathological conditions such as infectious or ocular disease, cancer, and genetic or metabolic disorders. These therapeutic methods are currently being a

phenomenon in cancer therapy because siRNA is used to suppress oncogenes and to remove mutations and to illuminate key molecules in the cellular pathways of cancer [1, 2].

It is also effective in personalized gene therapy for several diseases, due to its specificity, compatibility, and targeting ability. Following this strategic discovery, many synthetic siRNAs are designed with the desired sequences to explicitly inhibit any target gene expression [3, 4]. However, naked siRNA is unstable in the bloodstream and cannot effectively pass the cell membranes as well as being immunogenic [5].

There is a need for delivery systems in order to overcome the obstacles and to increase their potentials in the process of transporting siRNAs to the desired destination with minimal adverse effects and safe transportation to target areas. These carriers are usually provided with viral (retrovirus, lentivirus, adenovirus, adenoassociated virus (AAV), cough viruses, human foamy viruses, and baculovirus) and non-viral vectors. Viral vectors are effective tools for transfection vectors which are efficient delivery systems that utilize genetically modified viruses, offering advantages such as continuous gene silencing and the ease of expression of a large number of RNA interference (RNAi) molecules from a transcript [6, 7].

However, safety concerns such as oncogenicity, immunogenicity, viral genome insertion into host chromosomes, and expensive production limit the widespread use of viral vectors [8].

Until now, only one virus-mediated transport system has been authorized for marketing. Glybera® (alipogene tiparvovec using an adeno-associated virus as vector) was the first drug approved by the European Commission in late 2012 to treat lipoprotein lipase deficiency (LPLD). However, in early 2018, the most expensive drug in the world has been withdrawn from the market for financial reasons [9]. Therefore, it is important to design non-viral transport vectors for the in vivo delivery of siRNAs.

These delivery systems are mostly intended to make the siRNA more efficient for interaction with angiogenesis, metastasis, chemoresistance of tumors, and proliferation of cancer cells. Although these systems show encouraging results for possible therapeutic success, many obstacles still exist to implement them in humans, practically.

Delivery systems should not be immunogenic and should not cause undesirable side effects. In normal cells, siRNAs should avoid off-target silencing of genes [10].

The carrier systems should not be defined as foreign particles by the immune system elements, i.e., interferons and cytokines, and should not be eliminated before they reach the target. These difficulties have been overcome by the precise design of the siRNA to the target or by chemical modification of the relevant siRNA molecule.

For this reason, the use of lipidic/polymeric nanoparticles is the most common choice to overcome the above difficulties. These developed nanoparticles can protect the siRNA from plasmatic nucleases and unwanted immune responses, thereby facilitating endocytosis, designed to resist renal clearance; providing low cytotoxicity, stable serum stability, and high structural and functional reliability; delivering the unstable naked siRNA to targeted tumor sites; and reducing interactions with nontarget cells [7].

They can also be used for on-target delivery by adding target-specific ligands to their surface. The most preferred among these transport systems are lipid-based and polymer-based systems. Several technologies and nanoparticle modifications developed in recent years and new nanoparticle raw materials have accelerated the development of siRNA-loaded nanoparticles with the desired structural and functional properties.

**79**

**DRUG name**

CALAA-01 ALN-VSP02

Atu027 PRO-040201 TKM-080301

DCR-MYC

Hepatocellular carcinoma

Solid tumors, multiple myeloma,

MYC

LNP

1

NCT02110563

lymphoma

Advanced solid tumors

EphA2

NL

1

NCT01591356

siRNA-EphA2-

DOPC

ND-L02-s0201

Moderate to extensive hepatic

HSP47

LNP *KSP, kinesin spindle protein; VEGF, vascular endothelial growth factor; PEI, polyethylenimine; NP, neutral liposome; CD, cyclodextrin; PKN3, protein kinase N3; PLK1, polo-like kinase-1; ApoB, MYC* 

1

NCT01858935

fibrosis

*oncogene, apolipoprotein B; SNALP, stable nucleic acid lipid particle.*

**Table 1.**

*siRNA-based clinical trials using lipidic and polymeric vectors for cancer therapy [12, 13].*

MYC

LNP

1b/2

NCT02314052

Dicerna Pharmaceuticals,

Terminated

2014–2018

Terminated

2014–2017

Recruiting

2012–2018

Inc.

Dicerna Pharmaceuticals,

Inc.

M.D. Anderson Cancer

Center

Bristol-Myers Squibb

Completed

2014–2017

Primary or secondary liver cancer

PLK1

LNP

1

NCT01437007

Hypercholesterolemia

ApoB

SNALP

1

NCT00927459

Arbutus Biopharma Corporation National Cancer Institute (NCI)

Completed 2011–2018

Terminated 2009–2010

Advanced solid tumors

PKN3

LNP

1

NCT00938574

Silence Therapeutics GmbH

Completed 2009–2013

Solid tumors

KSP, VEGF

LNP

1

NCT00882180

Alnylam Pharmaceuticals

Completed 2009–2011

Solid tumors

RRM2

CD/polymer

1

NCT00689065

Calando Pharmaceuticals

Terminated 2008–2013

**Disease or condition**

**Target**

**Delivery vector**

**Phase**

**Trial number**

**Company**

**Recruitment status**

*Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery*

*DOI: http://dx.doi.org/10.5772/intechopen.86920*


#### *Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery DOI: http://dx.doi.org/10.5772/intechopen.86920*

*Antisense Therapy*

cancer [1, 2].

genic [5].

use of viral vectors [8].

delivery of siRNAs.

humans, practically.

molecule.

nontarget cells [7].

functional properties.

phenomenon in cancer therapy because siRNA is used to suppress oncogenes and to remove mutations and to illuminate key molecules in the cellular pathways of

It is also effective in personalized gene therapy for several diseases, due to its specificity, compatibility, and targeting ability. Following this strategic discovery, many synthetic siRNAs are designed with the desired sequences to explicitly inhibit any target gene expression [3, 4]. However, naked siRNA is unstable in the bloodstream and cannot effectively pass the cell membranes as well as being immuno-

There is a need for delivery systems in order to overcome the obstacles and to increase their potentials in the process of transporting siRNAs to the desired destination with minimal adverse effects and safe transportation to target areas. These carriers are usually provided with viral (retrovirus, lentivirus, adenovirus, adenoassociated virus (AAV), cough viruses, human foamy viruses, and baculovirus) and non-viral vectors. Viral vectors are effective tools for transfection vectors which are efficient delivery systems that utilize genetically modified viruses, offering advantages such as continuous gene silencing and the ease of expression of a large number

However, safety concerns such as oncogenicity, immunogenicity, viral genome insertion into host chromosomes, and expensive production limit the widespread

Until now, only one virus-mediated transport system has been authorized for marketing. Glybera® (alipogene tiparvovec using an adeno-associated virus as vector) was the first drug approved by the European Commission in late 2012 to treat lipoprotein lipase deficiency (LPLD). However, in early 2018, the most expensive drug in the world has been withdrawn from the market for financial reasons [9]. Therefore, it is important to design non-viral transport vectors for the in vivo

These delivery systems are mostly intended to make the siRNA more efficient for interaction with angiogenesis, metastasis, chemoresistance of tumors, and proliferation of cancer cells. Although these systems show encouraging results for possible therapeutic success, many obstacles still exist to implement them in

Delivery systems should not be immunogenic and should not cause undesirable side effects. In normal cells, siRNAs should avoid off-target silencing of genes [10]. The carrier systems should not be defined as foreign particles by the immune system elements, i.e., interferons and cytokines, and should not be eliminated before they reach the target. These difficulties have been overcome by the precise design of the siRNA to the target or by chemical modification of the relevant siRNA

For this reason, the use of lipidic/polymeric nanoparticles is the most common choice to overcome the above difficulties. These developed nanoparticles can protect the siRNA from plasmatic nucleases and unwanted immune responses, thereby facilitating endocytosis, designed to resist renal clearance; providing low cytotoxicity, stable serum stability, and high structural and functional reliability; delivering the unstable naked siRNA to targeted tumor sites; and reducing interactions with

They can also be used for on-target delivery by adding target-specific ligands to their surface. The most preferred among these transport systems are lipid-based and polymer-based systems. Several technologies and nanoparticle modifications developed in recent years and new nanoparticle raw materials have accelerated the development of siRNA-loaded nanoparticles with the desired structural and

of RNA interference (RNAi) molecules from a transcript [6, 7].

**78**

**Table 1.**

 *siRNA-based clinical trials using lipidic and polymeric vectors for cancer therapy [12, 13].*

Taking advantage of these excellent properties of nanoparticles, various delivery systems for siRNA have recently used the clinical trial phase, and these methods are followed as a very effective and promising treatment for various disease.

As the latest development in this issues, the US Food and Drug Administration approved the Onpattro (patisiran) infusion on 10 August 2018 for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment. FDA anticipates that this is the beginning of a new and exciting generation of therapeutics [11].

Patisiran is covered in a lipid nanoparticle (LNP) that carries the drug to the liver, but this carrier molecule can trigger its own immune response. Therefore, steroid, acetaminophen, and antihistamines should be used to reduce the likelihood of immune reaction in patients before taking patisiran administered by intravenous (IV) infusion. Further research is underway to design a drug delivery system that can reach the target tissue without causing an immune response. **Table 1** presents examples of clinical trials and current status of siRNAs prepared with lipidic and polymeric nanoparticle.
