Silica Nanoparticles as Drug Delivery System for Immunomodulator GMDP

E.V. ParfenyukN.A. AlyoshinaYu.S. AntsiferovaN.Yu. Sotnikova

Silica Nanoparticles as Drug Delivery System for Immunomodulator GMDP

BIoMeDIcal & NaNoMeDIcal TechNoloGIeS – coNcISe MoNoGraPh SerIeS

Silica Nanop

articles as Drug

Delivery System

for Imm

unomod

ulator GM

DP

Parfenyuk

Scope This concise monograph series focuses on the implementation of various engineering principles in the conception, design, development, analysis and operation of biomedical, biotechnological and nanotechnology systems and applications. Authors are encouraged to submit their work in the following core topics, but authors should contact the commissioning editor before submitting a proposal:

BIoMeDIcAL DeVIceS & MATeRIALS Trauma Analysis Vibration and Acoustics in Biomedical Applications Innovations in Processing, Characterization and

Applications of Bioengineered MaterialsViscoelasticity of Biological Tissues and Ultrasound

Applications Dynamics, and Control in Biomechanical Systems Clinical Applications of Bioengineering Transport Phenomena In Biomedical Applications Computational Modeling and Device Design Safety and Risk Analysis of Biomedical Engineering Modeling and Processing of Bioinspired Materials

and Biomaterials

NANoMeDIcAL DeVIceS & MATeRIALS Bio Nano Materials Nano Medical Sciences Materials for Drug & Gene Delivery Nanotechnology for Central Nervous System Nanomaterials & Living Systems Interactions Biosensing, Diagnostics & Imaging Cancer Nanotechnology Micro & Nano Fluidics Environmental Health & Safety Soft Nanotechnology & Colloids


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ISBN: 978-1-60650-421-5

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Contents

Introduction 1

1. Drug delivery nanosystems as a promising area of modern chemistry and medicine. Silica nanoparticles as potential drug carriers. 3

2. Syntheses of mesoporous silica materials. 82.1 Syntheses of unmodified silica materials 82.2 Synthesis of modified silica materials 10

3. Characterization of silica materials as potential carriers for GMDP. 123.1 Characterization of silica materials via FTIR spectroscopy 123.2 Characterization of silica materials via nitrogen

adsorption–desorption measurements 143.3 Particle size of silica materials 193.4 Characterization of silica materials via small angle x-ray

scattering (SAXS) 213.5 Adsorption properties of silica materials 213.6 DSC study of composites of model protein with silica

materials 263.7 Calorimetric study of adsorption of model protein on

silica materials 293.8 Preparation of silica nanoparticle suspensions 33

4. Interaction of silica nanoparticles with immune system cells. 354.1 Intensity of different silica nanoparticles uptake by

immune cells 354.2 Influence of silica nanoparticles on parameters of functional

activity of peritoneal macrophages 415. Peritoneal macrophages of women with endometriosis as

a possible target for immunomodulatory drugs. 445.1 Impairment of peritoneal macrophage function

at endometriosis 445.2 Influence of glucosaminyl muramyldipeptide

upon functional activity of peritoneal macrophages of women with endometriosis 48

Contents

6. Effectiveness of different types of silica nanoparticles as drug carriers for topical delivery of GMDP into peritoneal macrophages of women with endometriosis. 516.1 Immobilization of GMDP on silica nanoparticles 516.2 Comparative study of the effects of free GMDP and GMD

immobilized on silica nanoparticles on the functional state of peritoneal macrophages 52

References 59

Abstract

The development of nanosystems for topical drug delivery to target cells is a promising tool to improve the drug therapeutic index. Transport sys-tems can be designed to control the dispatch of the loaded drug to target areas, increasing its local concentration and bioavailability, while prolong-ing its retention, half-life and effectiveness. Therefore, such ‘‘smart’’ nano-devices are able to change radically the practice of therapy for a variety of diseases and disorders. The purpose of this book is to present the recent research development of nanoparticulate delivery systems for immune mod-ulating agent, glucosaminyl muramyldipeptides (N-acetylglucosaminyl-N-acetylmuramyl–L-alanyl-D-isoglutamine) or GMDP, which is the main component of bacterial wall with known target of action through NOD2 receptors, with an overlook to their applications for treatment of endometri-osis, which often results in infertility. Silica-based nanoparticles have gener-ated a significant amount of interest because of their inherent properties.

Acknowledgments

This work is supported by RFBR grants 09-03-97513 r_center_a; 12-04-97528 r_center_a.

NomenclatureAFM atomic force microscopy APTES 3-aminopropyl triethoxysilane BBB blood-brain barrierBET Brunauer-Emmett-Teller BJH Barrett-Joyner-HalendaBRB blood-retinal barrierCD cluster differentiation (CD14, CD45, CD11b, CD95, CD36,

CD86, CD204)Ct cycle threshold methodD-Ala D-alanineD-Glu D-glutamineD-isoGln D-isoglutamic acidDNA deoxyribonucleic acidDSC differential scanning calorimetry EPR enhanced permeability and etention effectFCA Freund’s Complete Adjuvan FITC fluoresceine isothiocyanate Fru fructose FTIR Fourier transform infrared spectroscopyGlcNAc N-acetylyglucoasamine GMDP N-acetylglucosaminyl-N-acetylmuramyl–L-alanyl-D-

isoglutamineHSA human serum albuminIEP isoelectric pointIFNg interferon gIgG immunoglobulinIL interleukin IUPAC International Union of Pure and Applied ChemistryLymph lymphocyteMacroph macrophageMCM-41 Mobil Catalytic Material number 41MDP muramyl dipeptide MMPs matrix metalloproteinases MTEOS methyl triethoxysilane MurNAc N-acetylmuramic acid NaCMC carboxymethylcellulose sodium salt NBT sp spontaneous NBT-testNBT st zymozan-stimulated NBT-testNOD2 nuclear-binding oligomerization domain 2PCR polymerase chain reaction methodPEG poly (ethelene glycole)PEI polyethelenimine

x Nomenclature

PolyG a 10-mer polyguanylic acidPVA polyvinyl alcoholRNA ribonucleic acidRPMI 1640 culture mediumSAXS small-angle x-ray scattering SHE Syrian hamster embryoSR-A, SR-B scavenger receptors of A and B typesSuc sucrose TEOS tetraehoxysilaneTDM trehalose-dimycolates TIMPs tissue inhibitors of matrix metalloproteinasesUV-VIS ultraviolet and visible spectroscopy

Introduction

The development of new drugs is one of the most important areas of modern chemistry and medicine. Much attention has been paid also to the increase of the efficiency of the already known drugs. One of the ways of solving this problem is the development of nanosystems for topical drug delivery to target cells. Drug delivery is a promising tool to improve the drug therapeu-tic index. Transport systems can be designed to control the dispatch of the loaded drug to target areas, increasing its local concentration and bioavail-ability, while prolonging its retention, half-life and effectiveness. Therefore, such ‘‘smart’’ nanodevices are able to change radically the practice of therapy for a variety of diseases and disorders.

The purpose of this book is to present the recent research development of nanoparticulate delivery systems for immune modulating agent, glucosami-nyl muramyldipeptides (N-acetylglucosaminyl-N-acetylmuramyl–L-alanyl-D-isoglutamine) or GMDP, which is the main component of a bacterial wall with a known target of action through NOD2 receptors, with an overview of their applications for treatment of endometriosis, which often results in infertility.

Silica-based nanoparticles have generated a significant amount of inter-est because of their inherent properties. The rigid structure of the inorganic component combined with the functionality of organic groups has yielded advanced materials with improved properties. The efficiency of drug deliv-ery nanosystems is directly related to the surface particles properties, to the intrinsic characteristics of the applied materials, and to the affinity between targeted drug and the particles surface. Therefore, special attention is fo-cused on the synthesis of silica particles and studies of their physiochemical properties, adsorption capability, and energy of binding of the drug with the particle surface. In vitro studies of interactions between the different types of immune cells and the silica nanoparticles enable elucidation of the influ-ence of surface properties, size of the particles and incubation time with the immune cells on their viability, as well as cellular uptake of the particles by different types of cells. To estimate effectiveness of the developed drug deliv-ery nanosystems, effects of free GMDP, or GMDP immobilized on the the silica nanoparticles, upon the functional activity of peritoneal macrophages of women with endometriosis as well as upon expression of mRNA, genes controlling the activity of macrophages were estimated and compared. Thus, studies on the selection of an optimal nanocarrier for the immune modulat-ing drug have been described step-by-step in the book.

Development of drug delivery nanosystems requires knowledge and expertise in different disciplines, such as colloidal chemistry, chemistry of materials, biology, and medicine. Preparation of this book would not have been possible without valuable contributions from the research group of the Laboratory of Chemistry of Hybrid Nanomaterials and Supramolecular

2 Silica Nanoparticles as Drug Delivery System

Systems of the G.A. Krestov Institute of Solution Chemistry of Russian Academy of Sciences, and from experts in the field of immunology re-search from the Laboratory of Clinical Immunology of the Federal State Institution “Ivanovo Research Institute of Maternity and Childhood named V.N.Gorodkov” of the Health and Social Development Ministry of the Russian Federation.

1. Drug delivery nanosystems as a promising area of modern chemistry and medicine. Silica nanoparticles as potential drug carriers.

In present time, besides searching for new pharmacologically active com-pounds, optimization of therapeutic indexes of well known drugs is a ma-jor challenge for many pharmaceutical companies. Often use of traditional drug formulations suffer from grave shortcomings such as poor solubility and bioavailability, rapid elimination from the blood, low specificity, neces-sity of overdoses and increased side effects, etc.

New technologies are applied for constructing innovative drug formula-tion. The strategy, often called drug delivery systems, allows improvement in the therapeutic index of both established and new drugs, and is based on an interdisciplinary approach that combines chemistry, pharmaceutics and medicine.

In recent years, the development of therapeutic nanoparticles for drug delivery has received great attention. Nanoparticles are colloidal particles that range in size from 10 to 1000 nm in diameter. They can serve as carriers for different pharmacologically active agents which can be entrapped, ad-sorbed or chemically attached [1,2]. The advantages of using nanoparticles for drug delivery applications result from their unique properties.

Firstly, nanoparticles, because of their small size, can easy penetrate through various biological barriers and attain target sites. In the medical sector, extensive research activity is in progress to develop particles, which can be used as efficient carriers for drug delivery through the skin barrier. The skin is refractive to most molecules, especially hydrophilic ones, despite the existence of trans-barrier pathways. It has been shown that controlled and reliable drug delivery across the skin barrier can be achieved with lipo-somes, metallic nanoparticles, dendrimers, nanoemulsions as well as ultra-adaptable, and stable hetero-aggregates [3]. Lademann et al. reported that nanoparticles are efficient carriers for drug delivery into the hair follicles. Whereas the intercellular penetration of particles seems to be unlikely, the hair follicle has been shown to be a relevant penetration pathway for par-ticles as well as an important long-term reservoir. It has been demonstrated that the penetration depth of the particles can be influenced by their size resulting in the possibility of a differentiated targeting of specific follicular structures. The hair follicle provides important target structures for drug delivery, regenerative medicine and immunomodulation [4]. Recent inves-tigations have provided evidence that intravenous administration of gold nanoparticles could pass across the blood-retinal barrier (BRB), which depends on the size of the nanoparticles, and this process induced no cy-totoxicity in the retina. After intravenous injection of gold nanoparticles into C57BL/6 mice, 100 nm nanoparticles were not detected in the retina


whereas 20 nm nanoparticles passed through the BRB and were distributed in all retinal layers. The nanoparticles detected in the retina were bound on to the membrane [5]. The nanoparticle-based drug delivery systems possess a significant potential for brain targeting [6–8]. It was shown that normally drugs are unable to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from passing through. However, the drugs can overcome this barrier after their immobilization onto nanocarriers. This provides a way for effective treatments of many common central nervous system disor-ders, such as stroke, tumours and Alzheimer’s.

Due to their small size, nanocarriers can improve the efficacy of short-half-life drugs. However, their size should be optimal. Large particles with diameters greater than 200 nm are usually sequestered by the spleen as a result of mechanical filtration, and are eventually removed by the cells of the phagocyte system, resulting in decreased blood circulation time. On the other hand, smaller particles with diameters less than 10 nm can also leave the systemic circulation through the permeable vascular endothelium in the lymph nodes. Particles ranging from 10 to 300 nm are optimal for intra-venous injection and demonstrate the most prolonged blood circulation times [9–11]. So, drug immobilization on nanocarriers of definite size and surface properties can extend the biological half-life of the drug which in turn can provide sustained release profiles up to 24 h and improve patient compliance with drug regimens.

Secondly, reduction of particle size to nanometer scale leads to increas-ing specific surface area. Because specific surface area of such materials is very high, this allows them to load up with greater amounts of therapeutic agent, and releasing them in a more reproducible and predictable manner. A successful nanodelivery system should have a high drug-loadingand hence, there has been increasing interest in the application of porous materials by making use of their high surface area. Porous nanoparticles are widely pro-posed as drug nanocontainers [12–14].

Thirdly, one of the major problems with drug formulation is solubility, which is an essential factor for drug effectiveness, independent of the admin-istration route. A large number of drugs are discarded from consideration in their early stages of development owing to poor solubility. Development of nanoparticle formulations for insoluble, or poorly soluble in water drugs, enables improved bioavailability and release rates, potentially reducing the amount of the dose required and increasing safety through reduced side ef-fects [15–17].

Finally, nanoparticles can provide targeted delivery of drugs to specific cells or sites in the body, where the pharmacological action is desired. Targeted delivery can be actively or passively achieved [6,18]. Drugs or drug delivery nanosystems can be passively targeted making use of the pathophysiological opportunities, i.e. through the EPR (Enhanced Permeability and Retention)

Drug Delivery Nanosystems 5

effect, or of the anatomical opportunities (catheters can be used to infuse nanoparticles to the target organ or tissues). On the other hand, therapeutic nanoparticles can be conjugated to a ligand, having selective affinity for rec-ognizing and interacting with a specific cell, to achieve active target-specific drug delivery. The attachment of targeting ligands to the particles provides specific particle–cell interactions and enhances cellular uptake. The targeted drug delivery nanosystems promotes enhanced drug accumulation in target tissue and cells, decreasing the dose of drug needed and reducing its side effects.

Drug delivery nanosystems are already starting to have an impact on healthcare. At the present time, drugs with improved delivery systems are about 25% of the world volume of drug sales. Different materials, such as lipids (liposomes), polymers (macromolecules, micelles or dendrimers) and viruses (viral-like nanoparticles) as well as metals, inorganic and organome-tallic compounds (gold, iron oxide, silica), etc. have been proposed as “smart” nanocarriers for drug delivery [6,19]. Among materials that have been in-vestigated for drug delivery, silica materials have received intensive attention. Amorphous colloidal and porous silica has been proposed as a drug delivery system due to its attractive properties. In recent years, much attention has been paid to mesoporous silica nanoparticles (with a pore diameter of 2–50 nm) as carriers for controlled drug delivery. Mesoporous silica shows many promising characteristics such as uniform and tunable pore and particle size, high surface area and large pore volume, stable structure which is resistant to heat, pH, mechanical stress [12,14]. Drug molecules could be well en-trapped by entering the mesoporous channels or passing through the pores into hollow spaces. The drug loading and its release kinetics are affected by the drug and pore size [20–22].

A great advantage of mesoporous silica materials is that these materials can be easily modified by various functional groups. The surface modifica-tion permits control over the surface properties of the mesoporous silica nanoparticles for specific guest molecules. It was found that drug loading and release rate could be readily adjusted by organic functionalization of mesoporous materials. The drug loading and the release rate of the loaded active compound are very important characteristics of any drug delivery sys-tem. Depending on the medicament type, different drug release rates are desirable. In some cases (e.g. pain relief ) an immediate release of the active substance is favoured. In other cases (e.g. anti-flammatory drugs) sustained or controlled release is important in order to maintain a constant concen-tration of the active compound in the plasma. Moritz et al. [23] found that modification of the internal surface of SBA-15 with sulfonic (–SO3H) groups resulted in a high degree of loading and a slow rate of release of metoprolol or papaverine because of interactions between the weak bases and the modified mesoporous surface. A similar effect has been found for amino-modified MCM-41 silica material as a carrier of ibuprofen [24]. So,


modification of the silica surface by functional groups of different natures permitcontrol of drug pharmacodynamics and pharmacokinetics and opti-mal selection of the drug nanocarrier.

Besides, chemical modification of particulate drug carriers is the most fre-quent way to impart in vivo longevity to the carriers. It has been emphasized that the clearance behavior and tissue distribution of intravenously injected nanocarriers are greatly controlled by their surface characteristics [9,25]. These parameters can influence the degree of particle self-association in the blood as well as particle opsonization in biological fluids. The size of a par-ticle may change substantially upon introduction into a protein-containin g medium (e.g., plasma) due to the opsonization process. Therefore, in the blood, particles and their aggregates should be small enough so that they are not removed from the circulation by simple filtration or by phagocytic cells. Silica nanoparticles modified by hydrophilic polymer such as poly ethelene glycols (PEG) or zwitterionic-polymer (polyCBAA) demonstrate an increased colloidal stability and protein resistant properties [26,27]. The hydrophilic polymers have been shown to protect the nanoparticles from interactions with blood components due to shielding of the charged sur-face, increased surface hydrophilicity and their capacity for steric repulsion (“brush-like” structures) [9,25–27].

Biodegradation studies have shown that partial degradation of mesopo-rous silica nanoparticles takes place 2–24 h after immersion of the particles in a simulated body fluid [28]. Silica materials are biocompatible [29–32]. However, the extent to which un- and modified mesoporous silica, and in-deed many other types of nanomaterials currently being studied, are toxic to mammalian cells has not yet been fully explored. The data reported in the literature are diverse. Firstly it should be noted that crystalline forms of silica (e.g. quartz, cristobalite) have greater toxic effects upon living or-ganisms than similarly sized amorphous forms [33,34]. Particles of several amorphous silica forms have been shown to induce morphological trans-formation of SHE (Syrian hamster embryo) cells [35], as well as oxidative stress response in human lung cancer cells [36]. However, amorphous silica nanoparticles ranging in size from 20 to 400 nm do not exert significant genotoxicity [37,38]. Numerous studies show that toxicity of silica nano-particles is affected by many factors: surface chemistry, porosity, particle size, concentration, time of incubation as well as the mode of administration into a living organism [12,36–40]. However, a general assessment of the tox-icity is hard to make a priori, and instead detailed testing has to be done for each individual nanocarrier and a measure of each material’s cytotoxicity including silica nanoparticles must be clearly defined.

Though highly dispersive amorphous silica is widely used clinically [41], silica nanoparticles have been proposed as potential nanocarriers for delivery of different therapeutics, e.g. metoprolol and papaverine [23], aspirin [42], ibuprofen [24], antioxidant enzymes [43], photosesitizers [44], genes [14],

Drug Delivery Nanosystems 7

etc. On the basis of the facts reported above, silica nanoparticles were cho-sen for the development of a delivery nanosystem for the immune modulat-ing drug glucosaminyl muramyldipeptide or GMDP.

GMDP (N-acetylglucosaminyl-N-acetylmuramyl–L-alanyl-D-isoglutamine) is the minimal active fragment of peptidoglycan of the cell wall of Gram-positive and Gram-negative bacteria. The molecular structure of GMDP is presented in Figure 1-1.

It is known that GMDP strongly stimulates reactions of adaptive and especially innate immune responses [45]. The immune modulating drug has been widely used for therapy of different chronic bacterial and virus infec-tions such as psoriasis [46,47]. However, a serious shortcoming of GMDP is the very rapid elimination from the organism due to its high hydrophilic-ity, and as result, a low drug bioavailability (7–13%). It has been proposed that development of an efficient nanocarrier for the drug can overcome this problem.

Figure 1-1 Molecular structure of GMDP.

2. Syntheses of mesoporous silica materials.

Efficient drug carriers should have a high loading capacity, to bind the drug strongly enough to prevent the drug from being released prior to reaching the target cell, without any loss of pharmacological activity of the drug. At the present time, sol–gel technology has been widely applied for preparing bioactive materials [48,49]. The sol–gel technology allows manipulation of the structure of materials at the molecular level. Its ability to precisely con-trol the nature of interfaces make it an interesting approach for a wide range of practical applications. Procedure of the synthesis is simple: a precursor (or precursor mixture) is mixed with water and a mutual solvent (mostly alcohol) in the presence of an acid or a base catalyst. Both the hydrolysis of the precursor and condensation of the hydrolysis products occur simultane-ously, resulting in the formation of siloxane bonds (ºSi–O–Siº) and a po-rous network of gel, with production of alcohol and water as by-products:

hydrolysisºSi−OR + H2O ® º Si−OH + ROH

alcohol condensationºSi−OR + OH−Siº ® ºSi−O−Siº + ROH

water condensationºSi−OH + OH−Siº ® ºSi−O−Siº + H2O

After further drying, the resulting material known as a xerogel is formed [48,49].

In this work the sol-gel method was applied to synthesize unmodified mes-oporous silica materials as well as those modified by various functional groups.2.1 Syntheses of unmodified silica materials.Unmodified silica materials were synthesized by two methods. In the first method tetraethoxysilane (TEOS) as a precursor was mixed with a water-alcohol mixture (molar ratio TEOS : H2O =1:2.5) and aqueous ammonia (25% wt.) was added as catalyst [50,51]. The following reactions occur:

catalystSi(OC2H5)4 + 4 H2O ® Si(OH)4 + 4 C2H5OH

Si(OH)4 + Si(OH)4 ® Si O Si

O O

O O

O O + H2O

Syntheses of Mesoporous Silica Materials 9

An alternative method is known as templated sol-gel synthesis, when the hydrolysis and condensation processes occur in the presence of a structure-forming agent or template. In the templated synthesis of silica materials, the template molecules are coated with a siloxane network forming a specified structure. Pores created after the removal of the template retain the morpho-logical and stereochemical features of the structure. So, the templated syn-thesis permits to obtain the possibility of obtaining materials with the same nature of matrix but different parameters of porous structure. Different molecules have been applied as templates (quaternary ammonium salts, polymers, amines, etc) [12,52,53]. In the present work polyhydroxyl com-pounds were used as templates. The polyhydroxyl templates were chosen because they are inexpensive, biocompatible and environmentally friendly. Mono- and disaccharides can be readily removed from as synthesized com-posites via water extraction at room temperature [54,55], which is very im-portant for the development of biomedical materials. It would be interesting to know whether the size of the polyhydroxyl templates has an influence on the porous structure of the silica materials. Therefore, monosaccharide fructose (Fru), disaccharide sucrose (Suc), polysaccharide carboxymethyl-cellulose sodium salt (NaCMC) and polyvinyl alcohol (PVA) were used as templates (Figure 2-1).

Figure 2-1 Molecular structure of template molecules.


The unmodified silica was achieved by HCl-catalyzed hydrolysis and polycondensation of TEOS in the presence of the templates (fructose and sucrose) as described elsewhere [55]. But in the procedure of the synthe-sis described here, the silica precursor was not prehydrolyzed. All compo-nents were mixed simultaneously. In this procedure, initial formation of Si(OH)4 molecules and silica nucleation occurs already in the presence of the templates. According to literature data [54,56], the presence of numer-ous hydroxyl groups in mono- and polysaccharides promotes condensation reaction with silanols produced in the course of hydrolysis of the precur-sor, thus providing silica nucleation on the polyhydroxyl compounds. Mass ratio of TEOS : template is 3 : 1. For polymer templates (NaCMC, PVA), their water solutions (1.5%wt) are added to the precursor. Pores and ca-nals in the materials appear after removal of the templates due to release of the space occupied by the template molecules. Removal of the templates by calcination at 5000C and washing with hot water results in the formation of mesoporous silica materials [57] hereinafter referred as Fru-silica, Suc-silica, NaCMC-silica, PVA-silica. The calcinated and washed samples are designed as (calc.) and (wash.), respectively. 2.2 Synthesis of modified silica materials.Modified silica materials were synthesized by co-hydrolysis and co-con-densation of TEOS and modifying agents (3-aminopropyl triethoxysilane (APTES) and methyl triethoxysilane (MTEOS)) [50,51]. Formation of the modified materials occurred due to co-hydrolysis of TEOS and the modifier:

Si(OC2H5)4 + 4 H2O ® Si(OH)4 + 4 C2H5OH

R−Si(OC2H5)3 + 3 H2O ® R−Si(OH)3 + 3 C2H5OH

and co-condensation of the products

R−Si(OH)3 + Si(OH)4 ® + Si O Si

O O

O O

OR H2O ,

where R = NH2 (CH2)3 or CH3 functional groups.

The synthesis of the aminopropyl-modified silica was carried out with-out the addition of a catalyst because the amino groups of the modifier are able to catalyze the process. The methyl-modified silica was synthesized in basic condition (aqua ammonia serves as the catalyst). Another amino- modified silica material was synthesized by adding of polyethelenimine

Syntheses of Mesoporous Silica Materials 11

(PEI) to TEOS. The process is also catalyzed by numerous amino groups of the polymer [50,51]. The synthesized materials will be hereinafter referred as APTES-modified silica, PEI-modified silica and methyl-modified silica.

Thus, a series of silica materials with different functional groups on their surface were synthesized. Their particles are schematically shown in Figure 2-2.

Figure 2-2 The synthesized silica particles with various func-tional groups.

E.V. ParfenyukN.A. AlyoshinaYu.S. AntsiferovaN.Yu. Sotnikova

Silica Nanoparticles as Drug Delivery System for Immunomodulator GMDP


Silica Nanop

articles as Drug

Delivery System

for Imm

unomod

ulator GM

DP

Parfenyuk

Scope This concise monograph series focuses on the implementation of various engineering principles in the conception, design, development, analysis and operation of biomedical, biotechnological and nanotechnology systems and applications. Authors are encouraged to submit their work in the following core topics, but authors should contact the commissioning editor before submitting a proposal:

BIoMeDIcAL DeVIceS & MATeRIALS Trauma Analysis Vibration and Acoustics in Biomedical Applications Innovations in Processing, Characterization and

Applications of Bioengineered MaterialsViscoelasticity of Biological Tissues and Ultrasound

Applications Dynamics, and Control in Biomechanical Systems Clinical Applications of Bioengineering Transport Phenomena In Biomedical Applications Computational Modeling and Device Design Safety and Risk Analysis of Biomedical Engineering Modeling and Processing of Bioinspired Materials

and Biomaterials

NANoMeDIcAL DeVIceS & MATeRIALS Bio Nano Materials Nano Medical Sciences Materials for Drug & Gene Delivery Nanotechnology for Central Nervous System Nanomaterials & Living Systems Interactions Biosensing, Diagnostics & Imaging Cancer Nanotechnology Micro & Nano Fluidics Environmental Health & Safety Soft Nanotechnology & Colloids


Three Park AvenueNew York, NY 10016, USAwww.asme.org

ISBN: 978-1-60650-421-5

9 781606 504215

90000

222 E. 46th Street, #203New York, NY 10017, USAwww.momentumpress.net

ASME PRESS | M

OM

ENTUM

PRESS

Silica Nanoparticles as Drug Delivery System for Immunomodulator GMDP

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