**3. Types of nanoparticulate delivery systems for siRNA delivery**

This section focuses on the biodegradable non-viral lipids and polymeric nanosystems used in the transport of synthetic siRNA. These nanoparticles used as

**83**

*3.1.2 Solid lipid nanoparticles*

*Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery*

polymers. The advantages thus outweigh the disadvantages [30].

**3.1 Lipid-based nanoparticle delivery systems**

between the fatty acyl chains of the two lipid layers [31].

drug delivery vehicles are carriers having a particle size of <100 nm. They are composed of different biodegradable materials, such as natural or synthetic polymers,

The main advantages of nanoparticles used as drug carriers are achieving appropriate particle size, using of physiological lipids (e.g., triglycerides) and organic polymers (e.g., chitosan) to reduce immunogenicity, stimulating interferon-γ production and natural killer (NK) cells, activating antitumor immunity to increase the effectiveness of treatment, prolongation of blood circulation in blood, and feasibility of variable routes of administration; they can be viewed and monitored by marking. However, they have some disadvantages; for example, the substances used during the formulation and the preparation methods may cause the increase of toxicity, sometimes failing to carry the siRNA into the cell or insufficient accumulation at the target site, and problems in the stability of lipidic structures like liposomes. These limitations, however, can be overcome by selecting the appropriate lipid or

Lipid-based siRNA delivery systems include liposomes, micelles, microemul-

Liposomes are spherical vesicles consisting of an aqueous core together with a bilayer phospholipid structure which contain natural body components (e.g., lipids, sterols) and are biologically compatible and biodegradable. Furthermore, liposomes are popular siRNA carriers due to their relative simplicity and well-known pharmaceutical properties. The amphipathic nature of liposomes allows the use of a wide range of hydrophilic and hydrophobic drugs. The hydrophilic molecules show a greater affinity between the hydrophilic head groups of the phospholipid bilayer and the aqueous core of the liposomes, while the hydrophobic molecules intercalate

As analogues of biological membranes, liposomes are fused with the plasma membrane and are processed by endocytosis, and the genetic material is released into the cytoplasm. Cationic liposomes form complexes with negatively charged anionic siRNAs and polycations, and the complex is called as a "lipoplex." However, due to their positive charge, cationic liposomes can lead to dosedependent cytotoxicity and inflammatory response, and the complexes can interact nonspecifically with negatively charged serum proteins. In order to solve these problems, successful tests were taken in preclinical studies of EphA2-targeted siRNA therapeutic using neutral lipids such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which proved to effectively reduce cellular toxicity [31].

Several strategies have been implemented to overcome the disadvantages of existing lipid-based systems. Modification of the lipid structure or formulation methods can reduce toxicity and improve transfection. The inclusion of fusogenic lipids, such as dioleoylphosphatidylethanolamine (DOPE), or the use of a cationic lipid consisting of biodegradable ester bonds such as DOTAP may retain toxic effects at a relatively short or moderate level and also may increase the endosomal release of siRNA [32].

SLNs having a size range of 50–1000 nm were composed from various lipids which are solid form at body or room temperature and can be stabilized with

sions, ionizable lipids and lipid nanoparticles, and solid lipid nanoparticles.

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

lipids, or metal.

*3.1.1 Liposomes*

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

drug delivery vehicles are carriers having a particle size of <100 nm. They are composed of different biodegradable materials, such as natural or synthetic polymers, lipids, or metal.

The main advantages of nanoparticles used as drug carriers are achieving appropriate particle size, using of physiological lipids (e.g., triglycerides) and organic polymers (e.g., chitosan) to reduce immunogenicity, stimulating interferon-γ production and natural killer (NK) cells, activating antitumor immunity to increase the effectiveness of treatment, prolongation of blood circulation in blood, and feasibility of variable routes of administration; they can be viewed and monitored by marking.

However, they have some disadvantages; for example, the substances used during the formulation and the preparation methods may cause the increase of toxicity, sometimes failing to carry the siRNA into the cell or insufficient accumulation at the target site, and problems in the stability of lipidic structures like liposomes. These limitations, however, can be overcome by selecting the appropriate lipid or polymers. The advantages thus outweigh the disadvantages [30].

### **3.1 Lipid-based nanoparticle delivery systems**

Lipid-based siRNA delivery systems include liposomes, micelles, microemulsions, ionizable lipids and lipid nanoparticles, and solid lipid nanoparticles.

## *3.1.1 Liposomes*

*Antisense Therapy*

by the concentration gradient.

sizes of about 150 nm [19].

The vectors carrying siRNA enter the tissue interstitium following extravasation. After entering the tissue interstitium, siRNA is moved to the target cells across the interstitial space. Transport along the vessel walls can occur via diffusion, convection through the capillary pores, and transcytosis. The diffusion is directed

One of the unique properties of tumor microvessels is leakage (6) from endothelial discontinuity. The pore size of tumor microvessels ranges from 100 to 780 nm in diameter. In contrast, microvessels in most normal tissues have less leakage. For example; the tight junctions between endothelial cells are generally <2 nm, and the pore size in the capillary venules is <6 nm, the endothelium of the renal glomeruli is 40–60 nm, and the sinusoidal endothelium in the liver and spleen has large pore

Leakage in tumor vessels increases siRNA/carrier extravasation, since the naked siRNA cannot enter the direct cell membrane due to its high molecular weight, large size, and negatively charged phosphate skeleton from the anionic cell membrane;

There is an evidence that endocytosis (8) plays an important role, although not all of the entry mechanisms are well understood. The most common endocytosis used by nanocarriers is clathrin-mediated endocytosis through endocytic route receptor [23]. Rejman et al. [24] showed that the size and nature of the carrier vector affect the internalization mechanism. Nanoparticles of about 1 μm size are taken up via macropinocytosis, and ~120 nm size are taken up via clathrin-mediated endocytosis, whereas nanoparticles ~90 nm are taken up via clathrin/caveolae-independent

Besides surface properties and size of the nanoparticles, surface modifications of the nanoparticles are also important in siRNA transport. The most important of these surface modifications is the coating of nanoparticles with PEG. The PEGylation is performed to keep the particles in the systemic circulation longer, and the positive results were obtained from until today. However, in addition to this positive effect, it has been reported that the increased PEGylation from 1–2 to 5% mol reduced the transfection efficiency by neutralizing the positive surface load

required for siRNA involvement instead of increasing the transfection [27].

order to be loaded to RNA-induced silencing complex (RISC) [28].

**3. Types of nanoparticulate delivery systems for siRNA delivery**

This section focuses on the biodegradable non-viral lipids and polymeric nanosystems used in the transport of synthetic siRNA. These nanoparticles used as

After reaching the target cell, the siRNA is subjected to endocytosis internalization, a process involving encapsulated siRNA in endocytic vesicles fused with endosomes. Endocytotic vesicles are initially associated with early endosomes and then mature late endosomes before fusion with lysosomes in the cell. Lysosomes are then formed. After internalization into the cell, the siRNA should escape from the fragmentation in the endosomes and be released from the carrier to the cytosol in

Sardo et al. found that endosomal escape increased with another modification with pH-sensitive polymers. In this study, they prepared a siRNA delivery system based on inulin (Inu), a plenty and natural polysaccharide. Inu was functionalized via the conjugation with diethylenetriamine (DETA) residues to form the complex Inu-DETA. The results of the study showed that while homogenous diffusion of siRNA was performed in JHH6 cytoplasm via micropinocytosis and clathrinmediated endocytosis, it was found that it did not allow caveola-mediated passage

the carrier systems are gaining importance here, again [21, 22].

endocytosis and caveolin-mediated endocytosis [25, 26].

**82**

and no siRNA activity [29].

Liposomes are spherical vesicles consisting of an aqueous core together with a bilayer phospholipid structure which contain natural body components (e.g., lipids, sterols) and are biologically compatible and biodegradable. Furthermore, liposomes are popular siRNA carriers due to their relative simplicity and well-known pharmaceutical properties. The amphipathic nature of liposomes allows the use of a wide range of hydrophilic and hydrophobic drugs. The hydrophilic molecules show a greater affinity between the hydrophilic head groups of the phospholipid bilayer and the aqueous core of the liposomes, while the hydrophobic molecules intercalate between the fatty acyl chains of the two lipid layers [31].

As analogues of biological membranes, liposomes are fused with the plasma membrane and are processed by endocytosis, and the genetic material is released into the cytoplasm. Cationic liposomes form complexes with negatively charged anionic siRNAs and polycations, and the complex is called as a "lipoplex."

However, due to their positive charge, cationic liposomes can lead to dosedependent cytotoxicity and inflammatory response, and the complexes can interact nonspecifically with negatively charged serum proteins. In order to solve these problems, successful tests were taken in preclinical studies of EphA2-targeted siRNA therapeutic using neutral lipids such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), which proved to effectively reduce cellular toxicity [31].

Several strategies have been implemented to overcome the disadvantages of existing lipid-based systems. Modification of the lipid structure or formulation methods can reduce toxicity and improve transfection. The inclusion of fusogenic lipids, such as dioleoylphosphatidylethanolamine (DOPE), or the use of a cationic lipid consisting of biodegradable ester bonds such as DOTAP may retain toxic effects at a relatively short or moderate level and also may increase the endosomal release of siRNA [32].

#### *3.1.2 Solid lipid nanoparticles*

SLNs having a size range of 50–1000 nm were composed from various lipids which are solid form at body or room temperature and can be stabilized with

#### *Antisense Therapy*

surfactant or surfactant mixture. SLNs consist of a lipid core surrounded by a surfactant layer in an aqueous dispersion [33].

While being among the most effective carriers for both hydrophilic and hydrophobic drugs, such as liposomes, the solid, lipophilic nucleus of SLNs may have difficulty carrying RNA molecules that are hydrophilic and polyanionic. Therefore, it can be used successfully for gene delivery by addition of cationic lipids to SLNs which provide a positive surface potential [34].

SLNs can be easily prepared by various methods such as hot or cold homogenization, sonication, solvent evaporation, etc., and also they have high physical stability and low cytotoxicity [35].

Studies with siRNAs that have been adsorbed or encapsulated into SLNs have also shown positive results in the literature. For example, Şenel et al. [36] pointed out that Bcl-2-targeted siRNAs encapsulated into SLNs prepared by sonication method showed an activity to be able to compete with Lipofectamine in the liposomal form commercially used.

#### *3.1.3 Nanostructured lipid carriers (NLCs)*

Nanostructured lipid carriers (NLCs) are new second-generation lipid carriers that combine the advantages of different nanocarriers. These are solid lipid-coremodified SLNs in which the lipid phase may comprise solid or liquid forms at ambient temperature [37].

Compared to SLNs, NLCs have greater loading capacity and less water in the dispersion, making them more stable for storage. There was no difference in biotoxicity. Studies have shown that NLCs can be used as a new delivery tool for the genetic treatment of disease. Taratula et al. prepared a multifunctional NLC system containing two siRNAs against cellular resistance to doxorubicin or paclitaxel targeting lung cancer cells. It has been found that the system successfully increases the antitumor activity of the anticancer drug [38, 39].

NLCs can also be modified to achieve targeting and sustained release. For example, by manipulating the degradation times of NLCs, it has made possible to obtain long-acting siRNAs. This design raised the continuous release of siRNAs to 9 days (with a A-tailored nanostructure carrier design delivering survivin-siRNA); this also facilitates clinical practice of siRNA treatment [40].

#### *3.1.4 Ionizable lipids and lipid nanoparticles (LNPs)*

Recently, new lipid types have been proposed to the delivery of RNA interference molecules. Advanced LNP siRNA systems are lipid-based particles with diameters <100 nm. These may consist of a mixture of an ionizable amino lipid (e.g., heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate, DLin-MC3-DMA), a phosphatidylcholine, cholesterol, and a coat lipid (polyethylene glycol-dimiris glycerol) in a 50:10:38.5:1.5 molar ratio [41].

These lipids developed for the encapsulation of negatively charged genetic materials exhibit pH-dependent charge change. These lipids are positive at acidic pH and are neutral at physiological pH. Thus, under acidic conditions, nucleic acids are encapsulated in the nanoparticle and have a minimum positive charge density in the bloodstream. LNP siRNA systems are produced by rapidly mixing the lipids in ethanol with the siRNA in aqueous buffer (pH 4.0) followed by removal of ethanol via dialysis against PBS buffer after the pH is raised to 7.4 [42].

The genetic material carrier formulations generated by ionizable cationic lipids have been shown to be of significant success in in vivo activity after the initial administration in hepatocytes. Other tissues used for gene silencing include

**85**

*Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery*

macrophages, osteoclasts, and osteoblasts in the "hard" bone and distal tumor

Other siRNA administration methods have used lipid-like molecules called "lipidoids" for the delivery of siRNA. Lipidoid delivery systems are similar to ionizable cationic LNP systems due to the use of lipid-like molecules, cholesterol, and PEG-lipid. The most important difference of LNPs using lipidoid is that the lipidoid molecules have an extra positive charge because they have a large number of protonizable amine bound to various acyl chains. Similar to studies with cationic lipids, lipidoid systems developed by screening programs have been described in the

Ball et al. developed a potent and nontoxic lipidoid nanoparticle (LNP) for intestinal epithelial cells. In the initial studies, it was reported that GAPDH siRNAloaded LNPs for Caco-2 cells mediated strong, dose-dependent, and resistant gene

Polymers of natural and synthetic origin have been used for various biomedical applications including drug targeting, imaging, gene therapy, prostheses, tissue engineering, etc. Because of their reproducible properties in terms of molecular weight, degradation, and mechanical properties, synthetic polymers are attractive for therapeutic applications. The most commonly used polymers include polyethylenimine (PEI), PLGA, PEG, PLL, PLA, etc. However, the synthetic polymers have the disadvantage biologically, such as they can turn into undesirable side effects or fail to achieve the desired bioactivity and biocompatibility. On the other hand, natural polymers are abundant and are similar to components of those found in biological extracellular matrices. Thus, the natural polymers have high bioactivity and biocompatibility. Natural polymers include polysaccharides, proteins, and

Linear or branched cationic polymers are effective transfection agents for genetic material. The structural and chemical properties of these polymers are well known. This makes them advantageous for siRNA transport. The positively charged polymers form "polyplexes" with negatively charged nucleic acid phosphates

The polymer size, the molecular weight, the degree of polymer branching, and the charge density, as well as the composition of the formulation medium and the positive and negative charges ratio between of the polymer and the oligonucleotides, affect the transfection efficiency and biological activity of the polyplexes. Synthetic-based cationic polymers such as PLL, PLA, and PEI are the most studied polymers for in vitro and in vivo transport of siRNA. The size of the complexes is one of the most important factors affecting cellular uptake. Due to their small size, the cationic polymers generally complex with the genetic material more effectively than lipids. In addition, owing to being mostly synthetic, they have some special feature such as customized size, branching, and composition, and these

These polymers used for siRNA delivery is well-studied, biodegradable, biocompatible, and capable of exhibiting nucleic acid sustained release in pharmaceutical

PEI was used to create cationic charges on the surface of PLGA particles, which

allowed the complexation of nucleic acids on the surface of the particles [50].

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

silencing with a single 10-nM dose for 1 week [46].

cells [43, 44].

literature [45].

polyesters [47].

*3.2.1 Synthetic polymers*

through electrostatic interactions [48].

features can be easily changed [49].

applications for decades.

**3.2 Polymer-based delivery**

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

macrophages, osteoclasts, and osteoblasts in the "hard" bone and distal tumor cells [43, 44].

Other siRNA administration methods have used lipid-like molecules called "lipidoids" for the delivery of siRNA. Lipidoid delivery systems are similar to ionizable cationic LNP systems due to the use of lipid-like molecules, cholesterol, and PEG-lipid. The most important difference of LNPs using lipidoid is that the lipidoid molecules have an extra positive charge because they have a large number of protonizable amine bound to various acyl chains. Similar to studies with cationic lipids, lipidoid systems developed by screening programs have been described in the literature [45].

Ball et al. developed a potent and nontoxic lipidoid nanoparticle (LNP) for intestinal epithelial cells. In the initial studies, it was reported that GAPDH siRNAloaded LNPs for Caco-2 cells mediated strong, dose-dependent, and resistant gene silencing with a single 10-nM dose for 1 week [46].

## **3.2 Polymer-based delivery**

*Antisense Therapy*

and low cytotoxicity [35].

mal form commercially used.

ambient temperature [37].

*3.1.3 Nanostructured lipid carriers (NLCs)*

the antitumor activity of the anticancer drug [38, 39].

*3.1.4 Ionizable lipids and lipid nanoparticles (LNPs)*

this also facilitates clinical practice of siRNA treatment [40].

glycol-dimiris glycerol) in a 50:10:38.5:1.5 molar ratio [41].

via dialysis against PBS buffer after the pH is raised to 7.4 [42].

surfactant or surfactant mixture. SLNs consist of a lipid core surrounded by a

While being among the most effective carriers for both hydrophilic and hydrophobic drugs, such as liposomes, the solid, lipophilic nucleus of SLNs may have difficulty carrying RNA molecules that are hydrophilic and polyanionic. Therefore, it can be used successfully for gene delivery by addition of cationic lipids to SLNs

SLNs can be easily prepared by various methods such as hot or cold homogenization, sonication, solvent evaporation, etc., and also they have high physical stability

Studies with siRNAs that have been adsorbed or encapsulated into SLNs have also shown positive results in the literature. For example, Şenel et al. [36] pointed out that Bcl-2-targeted siRNAs encapsulated into SLNs prepared by sonication method showed an activity to be able to compete with Lipofectamine in the liposo-

Nanostructured lipid carriers (NLCs) are new second-generation lipid carriers that combine the advantages of different nanocarriers. These are solid lipid-coremodified SLNs in which the lipid phase may comprise solid or liquid forms at

Compared to SLNs, NLCs have greater loading capacity and less water in the dispersion, making them more stable for storage. There was no difference in biotoxicity. Studies have shown that NLCs can be used as a new delivery tool for the genetic treatment of disease. Taratula et al. prepared a multifunctional NLC system containing two siRNAs against cellular resistance to doxorubicin or paclitaxel targeting lung cancer cells. It has been found that the system successfully increases

NLCs can also be modified to achieve targeting and sustained release. For example, by manipulating the degradation times of NLCs, it has made possible to obtain long-acting siRNAs. This design raised the continuous release of siRNAs to 9 days (with a A-tailored nanostructure carrier design delivering survivin-siRNA);

Recently, new lipid types have been proposed to the delivery of RNA interference molecules. Advanced LNP siRNA systems are lipid-based particles with diameters <100 nm. These may consist of a mixture of an ionizable amino lipid (e.g., heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate, DLin-MC3-DMA), a phosphatidylcholine, cholesterol, and a coat lipid (polyethylene

These lipids developed for the encapsulation of negatively charged genetic materials exhibit pH-dependent charge change. These lipids are positive at acidic pH and are neutral at physiological pH. Thus, under acidic conditions, nucleic acids are encapsulated in the nanoparticle and have a minimum positive charge density in the bloodstream. LNP siRNA systems are produced by rapidly mixing the lipids in ethanol with the siRNA in aqueous buffer (pH 4.0) followed by removal of ethanol

The genetic material carrier formulations generated by ionizable cationic lipids have been shown to be of significant success in in vivo activity after the initial administration in hepatocytes. Other tissues used for gene silencing include

surfactant layer in an aqueous dispersion [33].

which provide a positive surface potential [34].

**84**

Polymers of natural and synthetic origin have been used for various biomedical applications including drug targeting, imaging, gene therapy, prostheses, tissue engineering, etc. Because of their reproducible properties in terms of molecular weight, degradation, and mechanical properties, synthetic polymers are attractive for therapeutic applications. The most commonly used polymers include polyethylenimine (PEI), PLGA, PEG, PLL, PLA, etc. However, the synthetic polymers have the disadvantage biologically, such as they can turn into undesirable side effects or fail to achieve the desired bioactivity and biocompatibility. On the other hand, natural polymers are abundant and are similar to components of those found in biological extracellular matrices. Thus, the natural polymers have high bioactivity and biocompatibility. Natural polymers include polysaccharides, proteins, and polyesters [47].

#### *3.2.1 Synthetic polymers*

Linear or branched cationic polymers are effective transfection agents for genetic material. The structural and chemical properties of these polymers are well known. This makes them advantageous for siRNA transport. The positively charged polymers form "polyplexes" with negatively charged nucleic acid phosphates through electrostatic interactions [48].

The polymer size, the molecular weight, the degree of polymer branching, and the charge density, as well as the composition of the formulation medium and the positive and negative charges ratio between of the polymer and the oligonucleotides, affect the transfection efficiency and biological activity of the polyplexes.

Synthetic-based cationic polymers such as PLL, PLA, and PEI are the most studied polymers for in vitro and in vivo transport of siRNA. The size of the complexes is one of the most important factors affecting cellular uptake. Due to their small size, the cationic polymers generally complex with the genetic material more effectively than lipids. In addition, owing to being mostly synthetic, they have some special feature such as customized size, branching, and composition, and these features can be easily changed [49].

These polymers used for siRNA delivery is well-studied, biodegradable, biocompatible, and capable of exhibiting nucleic acid sustained release in pharmaceutical applications for decades.

PEI was used to create cationic charges on the surface of PLGA particles, which allowed the complexation of nucleic acids on the surface of the particles [50].

#### *Antisense Therapy*

In a study done by Patil and Panyam [51], siRNA encapsulation studies were performed in PLGA nanoparticles. These nanoparticles were prepared by the solvent evaporation method. In this method, a cationic polymer, PEI, was added to the PLGA matrix, and ultimately it has been reported that nanoparticles can penetrate into the cell at twice the rate.

Furthermore, cationic polymers with high charge densities have "proton sponge" properties that stimulate escape from endosomes and protect genetic materials from degradation. For example, PEI, by pulling and sustaining a significant amount of protons, induces osmotic swelling and rupture of endosomes, causing the genetic material to be released from the nanoparticles in the cytoplasm and thus preventing the transport to lysosomes and degradation of genetic material [52].

In another study, the hydrogel scaffold based on polyamidoamine (PAMAM) dendrimer cross-linked with dextran aldehyde was prepared to improve the stability of the nanoparticle. These nanoparticle systems were found to be effective for gene silencing [53].

#### *3.2.2 Natural polymers*

Many polysaccharides in natural Polymer structure are used for siRNA. Polysaccharides are generally biocompatible polymers. The main advantage is the presence of different functional groups (i.e., carboxyl, hydroxyl, amine) which enable functionalization to obtain structural heterogeneity and copolymers [54].

The most commonly used polysaccharides for siRNA administration include chitosan, which contains both biodegradable, biocompatible, low-cost, low cytotoxicity hydroxyl and amines. The presence of primary amino groups (pKa ≈ 6) makes the chitosan a polycation that promotes the association with nucleic acids and also the formation of polyplex [55].

In order to increase the solubility of chitosan, various modifications have been done and water-soluble chitololigosaccharides have been obtained. These chitololigosaccharides were used for delivery of the siRNA [35, 56].

Collagen is another biologically compatible and safe natural polymer and is a suitable carrier for drug delivery. In a study performed by Peng et al., localized and sustained release of siRNA-loaded collagen formulations were prepared for use in vivo gastric cancer, and positive results were obtained [57].

#### **3.3 Lipid-polymer hybrid nanoparticles**

Lipid-polymer hybrid nanoparticles (LPNs) were developed to eliminate the disadvantages of polymeric and lipid-based nanoparticles. The precious properties of LPNs containing polymer cores and lipid shells carry the complementary properties of both materials. In a study on the administration of LPNs in cancer treatment, the lipid/rPAA-Chol polymer hybrid nanoparticles were modified with PEG and T7 peptide; tumor has been shown to be largely inhibited without activating the immune system [58].

In another study, LPNs were used for the antitumoral effect in the pancreatic tumor model in combination with hypoxia-inducible factor 1α (HIF1alpha) targeted siRNA and gemitabicin. This prepared LPN complex showed an excellent ability to inhibit tumor metastasis in an orthotopic tumor model [59].

## **4. Conclusion**

In recent years, siRNA has been widely used as a promising therapeutic phenomenon to many pathological conditions. Progress has been made in researching target

**87**

**Author details**

Behiye Şenel\* and Gülay Büyükköroğlu

provided the original work is properly cited.

Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: behiyek@anadolu.edu.tr

*Applications of Lipidic and Polymeric Nanoparticles for siRNA Delivery*

genes and in the development of delivery systems for siRNA. However, challenges remain for successful clinical application of RNAi-based therapeutics. Safety concerns are the main reason for the withdrawal of clinical trials of some RNAi

Since its discovery, siRNA therapeutics have been actively used because of their high specificity, easy modifications, and unlimited therapeutic targets. However, the instability in the bloodstream and the problems with the accumulation in the target region necessitated the application of these therapeutics in a transport

The lipidic and polymeric nanoparticle systems described in this chapter are one step ahead the systems than other nanoparticle systems and have been proven to be of importance in these delivery processes in recent years. New modified systems are being developed to ensure safe and targeted distribution of siRNA. According to the results obtained from studies, new formulations are expected to reach clinical trials

The authors report no conflicts of interest. The authors alone are responsible for

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

therapies.

system.

very soon such as patisiran.

the content of and writing of this article.

**Conflict of interest**

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

genes and in the development of delivery systems for siRNA. However, challenges remain for successful clinical application of RNAi-based therapeutics. Safety concerns are the main reason for the withdrawal of clinical trials of some RNAi therapies.

Since its discovery, siRNA therapeutics have been actively used because of their high specificity, easy modifications, and unlimited therapeutic targets. However, the instability in the bloodstream and the problems with the accumulation in the target region necessitated the application of these therapeutics in a transport system.

The lipidic and polymeric nanoparticle systems described in this chapter are one step ahead the systems than other nanoparticle systems and have been proven to be of importance in these delivery processes in recent years. New modified systems are being developed to ensure safe and targeted distribution of siRNA. According to the results obtained from studies, new formulations are expected to reach clinical trials very soon such as patisiran.
