3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.4.Dendrimers
Dendrimers are small molecules which have a core and a series of branches symmetrically formed around the core resulting in a monodisperse, symmetrical macromolecule. They can be synthesized either starting from the core molecules and going out to the periphery by connecting the branch groups or by forming the branches first and then collecting all around the core. Functionality of the branching units is generally 2 or 3, which makes the layer of branching units doubles or triples. The interior cavity is very suitable for the entrapment of the drugs and their unique properties such as high degree of branching, multivalency, globular architecture and well-defined molecular weight, make dendrimers promising new carriers for drug delivery. Their nanometer size, ease of preparation and functionalization, and their ability to display multiple copies of surface groups for biological reorganization processes increase their attraction in biomedical applications.Interaction of dendrimer macromolecules with the molecular environment is predominantly controlled by their terminal groups. By modifying their termini, the interior of a dendrimer may be made hydrophilic while its exterior surface is hydrophobic, or vice versa. Drug molecules can be loaded both in the interior of the dendrimers as well as attached to the surface groups. Water-soluble dendrimers are capable of binding and solubilizing small molecules and can be used as coating agents to protect or deliver drugs to specific sites in the body or as time-release vehicles for transporting biologically active agents. In the last decades, research has increased on the design and synthesis of biocompatible dendrimers and their application to many areas of bioscience including drug delivery, immunology and the development of vaccines, antimicrobials and antivirals gained great attantion.A series of lipidic peptide dendrimers based on lysine with 16 surface alkyl (C12 ) chains has been synthesised by Florence et al (2000). A fourth generation dendrimer with a diameter of 2.5 nm was studied for its absorption at different organs after
แสดงบทความที่มีป้ายกำกับ Nanomaterials and Nanosystems แสดงบทความทั้งหมด
แสดงบทความที่มีป้ายกำกับ Nanomaterials and Nanosystems แสดงบทความทั้งหมด
วันจันทร์ที่ 8 มิถุนายน พ.ศ. 2552
3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.3.Ceramic Nanoparticles
Use of ceramics in medicine is especially significant in dental and orthopedic applications as strengthening materials for the hard tissue implants. Hydroxyapatite (HA) is a ceramic naturally existing in the bone structure and therefore its use in the hip or knee prosthesis can reduce the risk of rejection and stimulate the production of osteoblasts which are the cells responsible for the growth of the bone matrix.Ceramic particles effectively protect the doped molecules (enzymes, drugs, etc) against denaturation induced by external pH and temperature. In addition, their surfaces can be easily modified with different functional groups. They can be conjugated to a variety of monoclonal antibodies or ligands for targeting purposes in vivo. Ceramic particles with entrapped biomolecules have a great potential in delivery of drugs. Such particles, including silica, alumina, titania, etc, are known for their compatibility with biological systems. They have several advantages such as the ease of preparation with the desired size, shape and porosity under ambient conditions, high stability such as no swelling or change in shape in environmental conditions.McQuire et al (2005) synthesized hydroxyapatite sponges by using aminoacid coated HA nanoparticles dispersed within a viscous polysaccharide (dextran sulfate) matrix and examined the use of these materials for the viability and proliferation of human bone marrow stromal cells in order to search possibility for cartilage or soft tissue engineering. Rusu et al (2005) studied size-controlled hydroxyap- atite nanoparticles prepared in aqueous media in a chitosan matrix from soluble precursors salts bone for the purpose of tissue engineering applications. Serbetci et al (2000, 2002, 2004) prepared acrylic bone cements with addition of HA microparticles. They examined the effect of HA addition on the properties of the cement. They reported enhancement of mechanical, thermal and biological properties depending on the added amount of HA.Christel and co-workers (1984) implanted calcium phosphate bioglass ceramics in the tibiae of rabbits to study the interface of bioceramics. It was reported that hydroxyapatite surface give rise to a closer contact with new bone than calcium phosphate glass ceramics. Lin and colleagues (1996) implanted bioglass discs into the condyle area of rabbits. The failure load, when an implant detached from the bone or when the bone itself broke, was measured by a push-out test and compared with sintered hydroxyapatite bioceramic. Vogel and coworkers (2001) implanted bioglass particles in the distal femoral epiphysis of rabbits and examined bone formation at the implant site. They discussed the parameters (implantation model, particle size and surface-area-to-volume ratio) as possible parameters determining bone regeneration. Recently Amaral and colleagues (2002) studied wettability and surface charge properties of Si3 N4 –bioglass biocomposites. They determined that the examined bioglass had comparatively higher hydrophilic character and surface tension value than the most common bioceramics. The presence of very high negative zeta potential at neutral pH influenced albumin adsorption. They also studied mechanisms in terms of entropy and enthalpy gains from conformational unfolding and cation coadsorption (Amaral et al 2002).Zeng and co-workers (2002) prepared Al2 O3 –A/W bioglass coating through tape casting process by selecting low melting point A/W bioglass to decrease the Al2 O3 sintering temperature and modify the bioactivity of implant. On the other hand, Xin and colleagues (2005) investigated the formation of calcium phosphate (Ca-P) on various bioceramic surfaces in simulated body fluid (SBF) and in rabbit muscle. The bioceramics were sintered porous solids, including bioglass, glass-ceramics, hydroxyapatite, -tricalcium phosphate and -tricalcium phosphate. They compared the ability of inducing Ca-P formation and obtained similar results in SBF but observed considerable variations in vivo.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
3.3.Ceramic Nanoparticles
Use of ceramics in medicine is especially significant in dental and orthopedic applications as strengthening materials for the hard tissue implants. Hydroxyapatite (HA) is a ceramic naturally existing in the bone structure and therefore its use in the hip or knee prosthesis can reduce the risk of rejection and stimulate the production of osteoblasts which are the cells responsible for the growth of the bone matrix.Ceramic particles effectively protect the doped molecules (enzymes, drugs, etc) against denaturation induced by external pH and temperature. In addition, their surfaces can be easily modified with different functional groups. They can be conjugated to a variety of monoclonal antibodies or ligands for targeting purposes in vivo. Ceramic particles with entrapped biomolecules have a great potential in delivery of drugs. Such particles, including silica, alumina, titania, etc, are known for their compatibility with biological systems. They have several advantages such as the ease of preparation with the desired size, shape and porosity under ambient conditions, high stability such as no swelling or change in shape in environmental conditions.McQuire et al (2005) synthesized hydroxyapatite sponges by using aminoacid coated HA nanoparticles dispersed within a viscous polysaccharide (dextran sulfate) matrix and examined the use of these materials for the viability and proliferation of human bone marrow stromal cells in order to search possibility for cartilage or soft tissue engineering. Rusu et al (2005) studied size-controlled hydroxyap- atite nanoparticles prepared in aqueous media in a chitosan matrix from soluble precursors salts bone for the purpose of tissue engineering applications. Serbetci et al (2000, 2002, 2004) prepared acrylic bone cements with addition of HA microparticles. They examined the effect of HA addition on the properties of the cement. They reported enhancement of mechanical, thermal and biological properties depending on the added amount of HA.Christel and co-workers (1984) implanted calcium phosphate bioglass ceramics in the tibiae of rabbits to study the interface of bioceramics. It was reported that hydroxyapatite surface give rise to a closer contact with new bone than calcium phosphate glass ceramics. Lin and colleagues (1996) implanted bioglass discs into the condyle area of rabbits. The failure load, when an implant detached from the bone or when the bone itself broke, was measured by a push-out test and compared with sintered hydroxyapatite bioceramic. Vogel and coworkers (2001) implanted bioglass particles in the distal femoral epiphysis of rabbits and examined bone formation at the implant site. They discussed the parameters (implantation model, particle size and surface-area-to-volume ratio) as possible parameters determining bone regeneration. Recently Amaral and colleagues (2002) studied wettability and surface charge properties of Si3 N4 –bioglass biocomposites. They determined that the examined bioglass had comparatively higher hydrophilic character and surface tension value than the most common bioceramics. The presence of very high negative zeta potential at neutral pH influenced albumin adsorption. They also studied mechanisms in terms of entropy and enthalpy gains from conformational unfolding and cation coadsorption (Amaral et al 2002).Zeng and co-workers (2002) prepared Al2 O3 –A/W bioglass coating through tape casting process by selecting low melting point A/W bioglass to decrease the Al2 O3 sintering temperature and modify the bioactivity of implant. On the other hand, Xin and colleagues (2005) investigated the formation of calcium phosphate (Ca-P) on various bioceramic surfaces in simulated body fluid (SBF) and in rabbit muscle. The bioceramics were sintered porous solids, including bioglass, glass-ceramics, hydroxyapatite, -tricalcium phosphate and -tricalcium phosphate. They compared the ability of inducing Ca-P formation and obtained similar results in SBF but observed considerable variations in vivo.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.MICRO AND NANO SYSTEMS (cont)
3.2.Liposomes
Liposomes are small spherical vesicles in which one or more aqeous compart- ments are completely enclosed by molecules that have hydrophilic and hydrophobic functionality such as phospholipids and cholesterol. Properties of liposomes vary substantially with composition, size, surface charge and method of preparation. They can be formed as single lipid bilayer or in multiple bilayers. Liposomes containing one bilayer membrane are termed small unilamellar vesicles (SUV) or large unilamellar vesicles (LUV) based on their size ranges (Mozafari and Sahin2005). If more than one bilayer is present then they are called multilamellar vesicles (MLV). Liposomes are commonly used as model cells or carriers for various bioactive agents including drugs, vaccines, cosmetics and nutraceuticals.The introduction of positively or negatively charged lipids provides the liposomes a surface charge. Drugs associated with liposomes have markedly altered pharma- cokinetic properties compared to free drugs in solution. Liposomes are also effective in reducing systemic toxicity and preventing early degradation of the encapsu- lated drug after introduction to the body. They can be covered with polymers such as polyethylene glycol (PEG) – in which case they are called pegylated or stealth liposomes – and exhibit prolonged half-life in blood circulation (Mozafari et al 2005). Furthermore, liposomes can be conjugated to antibodies or ligands to enhance target-specific drug therapy. Visser et al (2005) studied targeting of pegylated liposomes loaded with horse radish peroxidase (HRP) and tagged with transferrin to the blood-brain barrier in vitro. They have shown effective targetting of liposomes loaded with protein or peptide drugs to the brain capillary endothelialcells and suggested that the system is an attractive approach for drug delivery to brain. Lopez-Pinto and coworkers (2005) examined the dermal delivery of a lipophilic drug, minoxidil, from ethosomes versus classic liposomes by appliying the vesicles non-occlusively on rat skin. They studied the permeation pattern, depth into the skin and the main permeation pathway of different liposomal systems. Ozden and Hasirci (1991) prepared small unilamellar vesicles composed of phosphatidyl- choline, dicetyl phosphate and cholesterol and entrapped glucose oxidase in them. They obtained loading efficiency as one protein per liposomal vesicle.Liposomes containing the expression vector pRSVneo coding for neomycin phosphotransferase–II were studied by Leibiger et al (1991) for a gene transfer into rat liver cells in vivo. After intravenous application of liposomes to male Wistar-rats, nonintegrated vector DNA was detected by blot-hybridisation in isolated nuclei of hepatocytes. Cirli and Hasirci (2004) prepared calcein encapsulated reverse phase evaporation vesicles carrying photoactive destabilization agent suprofen in the lipid bilayer. They investigated the effect of UV photoactivation of liposomal membrane- incorporated suprofen on the destabilization of the liposome bilayer and the release of encapsulated calcein as a model active agent.Liposomes are also studied as carriers for cells, genes or DNA fragments. Ito et al (2004) studied the effect of magnetite cationic liposomes which have positive surface charge to enrich and proliferate Mesenchymal stem cells (MSCs) in vitro. Kunisawa et al (2005) established a protocol for the encapsulation of nanoparticles in liposomes, which were further fused with ultra violet-inactivated Sendai virus to compose fusogenic liposomes and observed that fusogenic liposome demonstrated a high ability to deliver nanoparticles containing DNA into cytoplasm. Ito et al (2005) investigated whether coating the culture surface with RGD (Arg–Gly–Asp) conju- gated magnetite cationic liposomes (RGD-MCLs) was able to facilitate cell growth, cell sheet construction and cell sheet harvest using magnetic force without enzymatic treatment. They reported that cells adhered to the RGD-MCLs coated bottom of the culture surface, spreaded and proliferated to confluency. Detachment and harvesting of the cells did not need enzymatic process. Fuentes et al (2003) studied the adjuvan- ticity of two gamma inulin/liposomes/Vitamin E combinations in the mouse, in contraceptive vaccines by using sperm protein extracts or a synthetic HE2 peptide (Human Epididymis gene product; residues 15–28) as antigen. They showed that the gamma inulin/liposomes/Vitamin E combination, with sperm protein extracts, was better than Freund’s adjuvant. When the synthetic HE2 peptide was used as antigen, the gamma inulin/liposomes/Vitamin E combination was less effective than Freund’s adjuvant.Vierling et al (2001) published a review on fluorinated liposomes made from highly fluorinated double-chain phospho- or glyco-lipids as well as fluorinated lipoplexes, e.g. complexes made from highly fluorinated polycationic liposper- mines and a gene. The properties of the fluorinated lipoplexes including stability and in vitro cell transfection in the presence of serum or bile were reported. El Maghraby et al (2004) showed that incorporation of activators (surfactants) into liposomes improved estradiol vesicular skin delivery. They examined the interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes by using high sensitivity differential scanning calorimetry. Lopes and colleagues (2004) investigated the encapsulation of acid (AD) and sodium diclofenac (SD) in small unilamellar liposomes (SUV) prepared by sonication from multilamellar liposomes containing soya phosphatidylcholine and diclofenac at various propor- tions. The interactions of the drug with the bilayers were examined. They proposed a schematic model for interaction of SD with phosphatidylcholine of the liposomes in which the diclofenac anion interacts with the ammonium group of the phospho- lipid and the dichlorophenyl ring occupies a more internal site of bilayer near phosphate group. Simard et al (2005) prepared multilamellar vesicles by shearing a lamellar phase of lipids and surfactants. They reported formation of vesicles with mean diameter of less than 300 nm in which hydrophilic drugs can be loaded with high yield. They coated the vesicles with PEG and loaded them with 1-d-arabinofuranosylcytosine. Following injection of the vesicles intravenously to rats they observed that the surface-modified liposomes exhibited longer circulation times compared to uncoated liposomes.Koynova and MacDonald (2005) examined the lipid exchange between model lipid systems, including vesicles of the cationic lipoids ethyl dimyristoyl phosphatidylcholine, ethyl dipalmitoyl phosphatidylcholine or their complexes with DNA, and the zwitterionic lipids by using differential scanning calorimetry. They observed that, exchange via lipid monomers was considerably more facile for the cationic ethylphosphatidylcholines than for zwitterionic phosphatidylcholines and for the cationic liposomes. The presence of serum in the dispersing medium strongly promoted lipid transfer between cationic vesicles while almost no effect was reported for zwitterionic liposomes. This phenomenon was proposed as an important point for the application of cationic liposomes as nonviral gene delivery. Foco et al (2005) studied the delivery of sodium ascorbyl phosphate (SAP), an effective oxygen species scavenger to prevent the degenerative effects of UV radiation on skin. SAP was encapsulated into liposomes to improve its penetration through the stratum corneum into the deeper layers of the skin. They prepared two types of multilamellar vesicles, one from non-hydrogenated and the other from hydrogenated soybean lecithin, together with cholesterol. Sinico et al (2005) studied transdermal delivery of tretinoin and examined the influence of liposome composition, size, lamellarity and charge on transdermal delivery. They studied positively or negatively charged liposomes of different types, i.e. multilamellar vesicles (MLV) or unilamellar vesicles (ULV), prepared from hydrogenated soy phosphatidylcholine (Phospholipon® 90H) or non-hydrogenated soy phosphatidyl- choline (Phospholipon® 90) and cholesterol, in combination with stearylamine or dicetylphosphate. It was reported that negatively charged liposomes strongly improved newborn pig skin hydration and tretinoin retention.Arcon et al (2004) encapsulated an anticancer agent, cisplatin, in sterically stabilized liposomes and studied the systems with extended X-ray absorption fine structure (EXAFS) method, and concluded that the liposome-encapsulated drug is chemically stable and does not hydrolyze. Sapra and Allen (2003) published a review article about the ligand-targeted liposomes (LTLs) for the delivery of anticancer drugs. In this article, new approaches used in the design and optimization of LTLs was discussed and the advantages and potential problems associated with their therapeutic applications were described.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
3.2.Liposomes
Liposomes are small spherical vesicles in which one or more aqeous compart- ments are completely enclosed by molecules that have hydrophilic and hydrophobic functionality such as phospholipids and cholesterol. Properties of liposomes vary substantially with composition, size, surface charge and method of preparation. They can be formed as single lipid bilayer or in multiple bilayers. Liposomes containing one bilayer membrane are termed small unilamellar vesicles (SUV) or large unilamellar vesicles (LUV) based on their size ranges (Mozafari and Sahin2005). If more than one bilayer is present then they are called multilamellar vesicles (MLV). Liposomes are commonly used as model cells or carriers for various bioactive agents including drugs, vaccines, cosmetics and nutraceuticals.The introduction of positively or negatively charged lipids provides the liposomes a surface charge. Drugs associated with liposomes have markedly altered pharma- cokinetic properties compared to free drugs in solution. Liposomes are also effective in reducing systemic toxicity and preventing early degradation of the encapsu- lated drug after introduction to the body. They can be covered with polymers such as polyethylene glycol (PEG) – in which case they are called pegylated or stealth liposomes – and exhibit prolonged half-life in blood circulation (Mozafari et al 2005). Furthermore, liposomes can be conjugated to antibodies or ligands to enhance target-specific drug therapy. Visser et al (2005) studied targeting of pegylated liposomes loaded with horse radish peroxidase (HRP) and tagged with transferrin to the blood-brain barrier in vitro. They have shown effective targetting of liposomes loaded with protein or peptide drugs to the brain capillary endothelialcells and suggested that the system is an attractive approach for drug delivery to brain. Lopez-Pinto and coworkers (2005) examined the dermal delivery of a lipophilic drug, minoxidil, from ethosomes versus classic liposomes by appliying the vesicles non-occlusively on rat skin. They studied the permeation pattern, depth into the skin and the main permeation pathway of different liposomal systems. Ozden and Hasirci (1991) prepared small unilamellar vesicles composed of phosphatidyl- choline, dicetyl phosphate and cholesterol and entrapped glucose oxidase in them. They obtained loading efficiency as one protein per liposomal vesicle.Liposomes containing the expression vector pRSVneo coding for neomycin phosphotransferase–II were studied by Leibiger et al (1991) for a gene transfer into rat liver cells in vivo. After intravenous application of liposomes to male Wistar-rats, nonintegrated vector DNA was detected by blot-hybridisation in isolated nuclei of hepatocytes. Cirli and Hasirci (2004) prepared calcein encapsulated reverse phase evaporation vesicles carrying photoactive destabilization agent suprofen in the lipid bilayer. They investigated the effect of UV photoactivation of liposomal membrane- incorporated suprofen on the destabilization of the liposome bilayer and the release of encapsulated calcein as a model active agent.Liposomes are also studied as carriers for cells, genes or DNA fragments. Ito et al (2004) studied the effect of magnetite cationic liposomes which have positive surface charge to enrich and proliferate Mesenchymal stem cells (MSCs) in vitro. Kunisawa et al (2005) established a protocol for the encapsulation of nanoparticles in liposomes, which were further fused with ultra violet-inactivated Sendai virus to compose fusogenic liposomes and observed that fusogenic liposome demonstrated a high ability to deliver nanoparticles containing DNA into cytoplasm. Ito et al (2005) investigated whether coating the culture surface with RGD (Arg–Gly–Asp) conju- gated magnetite cationic liposomes (RGD-MCLs) was able to facilitate cell growth, cell sheet construction and cell sheet harvest using magnetic force without enzymatic treatment. They reported that cells adhered to the RGD-MCLs coated bottom of the culture surface, spreaded and proliferated to confluency. Detachment and harvesting of the cells did not need enzymatic process. Fuentes et al (2003) studied the adjuvan- ticity of two gamma inulin/liposomes/Vitamin E combinations in the mouse, in contraceptive vaccines by using sperm protein extracts or a synthetic HE2 peptide (Human Epididymis gene product; residues 15–28) as antigen. They showed that the gamma inulin/liposomes/Vitamin E combination, with sperm protein extracts, was better than Freund’s adjuvant. When the synthetic HE2 peptide was used as antigen, the gamma inulin/liposomes/Vitamin E combination was less effective than Freund’s adjuvant.Vierling et al (2001) published a review on fluorinated liposomes made from highly fluorinated double-chain phospho- or glyco-lipids as well as fluorinated lipoplexes, e.g. complexes made from highly fluorinated polycationic liposper- mines and a gene. The properties of the fluorinated lipoplexes including stability and in vitro cell transfection in the presence of serum or bile were reported. El Maghraby et al (2004) showed that incorporation of activators (surfactants) into liposomes improved estradiol vesicular skin delivery. They examined the interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes by using high sensitivity differential scanning calorimetry. Lopes and colleagues (2004) investigated the encapsulation of acid (AD) and sodium diclofenac (SD) in small unilamellar liposomes (SUV) prepared by sonication from multilamellar liposomes containing soya phosphatidylcholine and diclofenac at various propor- tions. The interactions of the drug with the bilayers were examined. They proposed a schematic model for interaction of SD with phosphatidylcholine of the liposomes in which the diclofenac anion interacts with the ammonium group of the phospho- lipid and the dichlorophenyl ring occupies a more internal site of bilayer near phosphate group. Simard et al (2005) prepared multilamellar vesicles by shearing a lamellar phase of lipids and surfactants. They reported formation of vesicles with mean diameter of less than 300 nm in which hydrophilic drugs can be loaded with high yield. They coated the vesicles with PEG and loaded them with 1-d-arabinofuranosylcytosine. Following injection of the vesicles intravenously to rats they observed that the surface-modified liposomes exhibited longer circulation times compared to uncoated liposomes.Koynova and MacDonald (2005) examined the lipid exchange between model lipid systems, including vesicles of the cationic lipoids ethyl dimyristoyl phosphatidylcholine, ethyl dipalmitoyl phosphatidylcholine or their complexes with DNA, and the zwitterionic lipids by using differential scanning calorimetry. They observed that, exchange via lipid monomers was considerably more facile for the cationic ethylphosphatidylcholines than for zwitterionic phosphatidylcholines and for the cationic liposomes. The presence of serum in the dispersing medium strongly promoted lipid transfer between cationic vesicles while almost no effect was reported for zwitterionic liposomes. This phenomenon was proposed as an important point for the application of cationic liposomes as nonviral gene delivery. Foco et al (2005) studied the delivery of sodium ascorbyl phosphate (SAP), an effective oxygen species scavenger to prevent the degenerative effects of UV radiation on skin. SAP was encapsulated into liposomes to improve its penetration through the stratum corneum into the deeper layers of the skin. They prepared two types of multilamellar vesicles, one from non-hydrogenated and the other from hydrogenated soybean lecithin, together with cholesterol. Sinico et al (2005) studied transdermal delivery of tretinoin and examined the influence of liposome composition, size, lamellarity and charge on transdermal delivery. They studied positively or negatively charged liposomes of different types, i.e. multilamellar vesicles (MLV) or unilamellar vesicles (ULV), prepared from hydrogenated soy phosphatidylcholine (Phospholipon® 90H) or non-hydrogenated soy phosphatidyl- choline (Phospholipon® 90) and cholesterol, in combination with stearylamine or dicetylphosphate. It was reported that negatively charged liposomes strongly improved newborn pig skin hydration and tretinoin retention.Arcon et al (2004) encapsulated an anticancer agent, cisplatin, in sterically stabilized liposomes and studied the systems with extended X-ray absorption fine structure (EXAFS) method, and concluded that the liposome-encapsulated drug is chemically stable and does not hydrolyze. Sapra and Allen (2003) published a review article about the ligand-targeted liposomes (LTLs) for the delivery of anticancer drugs. In this article, new approaches used in the design and optimization of LTLs was discussed and the advantages and potential problems associated with their therapeutic applications were described.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.MICRO AND NANO DRUG DELIVERY SYSTEMS(cont.)
3.1.Micelles
Micelles are ideal bioactive nanocarriers, especially for water insoluble agents. Many amphiphilic block copolymers can be used for this purpose. Polymers can self-associate to form spherical micelles in aqueous solution by keeping hydrophilic ends as the outer shell and the hydrophobic ends as the core. Hydrophobic drugs can be entrapped in the core during micelle formation process. Polymeric micelles have good thermodynamic stability in
physiological solutions, as indicated by their low critical micellar concentration, which makes them stable and prevents their rapid dissociation in vivo. The sizes of micelles are generally less than 100 nm in diameter. This provides them with long-term circulation in blood stream and enhanced endothelial cell ermeability in the vicinity of solid tumors by passive diffusion. If site-specific ligands or antibodies are conjugated to the surface of the micelles, the drug targeted delivery potential of polymeric micelles can be enhanced.Kataoka et al (2000) studied the effective targeting of cytotoxic agents to solid tumors by polymeric micelles. They conjugated doxorubicin to poly(ethylene glycol)-poly( , -aspartic acid) block copolymers and showed that these micelles achieved prolonged circulation in the blood compartment and accumulated more in
the solid tumor, leading to complete tumor regression against mouse C26 tumor. Rapoport (1999) studied stabilization and activation of Pluronic micelles for tumor- targeted drug delivery. Aliabadi et al (2005a) examined
the potential of polymeric micelles to modify the pharmacokinetics and tissue distribution of cyclosporine A (CsA). Their results demonstrated that PEO-b-PCL micelles can effectively solubilize CsA confining CsA to the blood circulation and restricting its access to tissues such as kidney, perhaps limiting the onset of toxicity. They also investigated micelles of methoxy poly (ethylene oxide)–b–poly ( –caprolactone) (PEO–b–PCL) as alternative vehicles for the solubilization and delivery of Cyclosporine A (Aliabadi et al 2005b). They concluded that these nanoscopic PEO–b–PCL micelles have high potential as drug carriers for efficient solubilization and controlled delivery of CsA. Prompruk et al (2005) synthesized a functionalized copolymer with three polymeric components,poly (ethylene glycol)–block–poly (aspartic acid–stat- phenylalanine) and investigated its potential to form micelles via ionic interactions with diminazene aceturate as a model water-soluble drug.Wasylewska et al (2004) entrapped human prostatic acid phosphatase (PAP)entrapped in AOT–isooctane–water reverse micelles and studied the kinetics of1–naphthyl phosphate and phenyl phosphate hydrolysis, catalyzed by PAP. Wang et al (2004) prepared polymeric micelles from poly (ethylene glycol)–distearoyl phosphoethanolamine conjugates (PEG–DSPE) loaded with
Vitamin K3 (VK3) and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). These micelles were stable for 6 months during storage at 4°C and no change in their size or release of the incorporated drugs were observed. They showed that these loaded micelles resulted in synergistic anticancer effects against both murine and human cancer cells in vitro. Kang et al (2004) prepared A-B-A triblock and star-block amphiphilic copolymers such as poly (N–(2–hydroxypropyl) methacrylamide)–block–poly (D,L–lactide)–block–poly (N–(2–hydroxy propyl) methacrylamide), poly (N–vinyl-2–pyrrolidone)–block–poly (D,L–lactide)–block–poly (N–vinyl–2–pyrrolidone), star–poly (D,L–lactide)–block–poly
(N–(2–hydroxypropyl) methacryl amide) and star–poly (D,L–lactide)–block–poly (N–vinylpyrrolidone). They reported that all copolymers self-assembled in aqueous solution to form supramolecular aggregates of 20–180 nm in size. The prepared triblock copolymer micelles were examined as carriers for two drugs, indomethacin and paclitaxel, which are poorly water- soluble. Carrillo and Kane (2004) studied the formation and characterization of self– assembled nanoparticles of controlled sizes based on amphiphilic block copolymers synthesized by ring-opening metathesis polymerization. They showed that the monomer undergoes living polymerization and forms assembled nanoparticles of controlled size. The obtained micelles were fairly monodisperse with dimensions of 30–80 nm depending on the composition of the block polymer.Synthetic copolymers containing phosphorylcholine structure can also be used in the formation of micelles. Phosphorylcholine-based polymers mimic the surface of natural phospholipid membrane bilayers and therefore
demonstrate good biocom- patability. Salvage et al (2005) copolymerised 2-methacryloyloxyethyl phospho- rylcholine (MPC) with two pH responsive comonomers, 2–(diethylamino) ethyl methacrylate (DEA) and 2–
(diisopropyl amino) ethyl methacrylate (DPA), in order to develop pH responsive biocompatible drug delivery vehicles. Koo et al (2005) studied sterically stabilized micelles (SSM) and evaluated camptothecin- containing SSM CPT–SSM) as a new nanomedicine for parenteral administration where camptothecin is a well-established topoisomerase I inhibitor against a broad spectrum of cancers. Konno et al (2001) have shown that 2-ethacryloyloxyethyl phosphorylcholine (MPC) polymer immobilized on poly (l–lactic acid) nanopar- ticles effectively suppressed any unfavourable interactions with biocomponents and improved the blood compatibility of the nanoparticles. It has been suggested that the nanoparticles immobilized with the MPC polymer have the potential use as long–circulating micelles and are good candidates for carrying drugs and diagnostic reagents which can come in contact with blood components. Nishiyama et al (2005) published a review article about
construction and characteristic behaviors of intracellular environment-sensitive micelles that selectively exert drug activity and gene expression in live cells. Xiong et al (2005) grafted poly (lactic acid) to both ends of
Pluronic F87 block copolymer (PEO–PPO–PEO) to obtain amphiphilic P(LA-b-EO-b-PO-b-EO-b-LA) block copolymers. Various types of particles consisting of small micelles were obtained due to the complex structure of the copolymers and a constant initial release rates were observed for procain hydrochloride. Sot and coworkers (2005) investigated the behaviour of N–hexadecanoyl sphingosine (Cer16), N–hexanoylsphingosine (Cer6) and N–acetyl sphingosine (Cer2) ceramides in aqueous media and in lipid-water systems. Cer16 behaved as an insoluble non-swelling amphiphile while both Cer6 and Cer2 behaved as soluble amphiphiles in aqueous solutions. They observed micelle formations for Cer6 and Cer2 at high concentrations as well as phospholipid monolayer formation when the air-water interface is occupied by a phospholipid.Responsivity can be added to micelles by combining pH or temperature sensitive functional groups into the structures. Cammas et al (1997) prepared thermo- responsive polymeric micelles from amphiphilic block copolymers composed of N–isopropylacrylamide as a thermo-responsive outer shell and styrene as hydrophobic inner core. Leroux et al (2001) studied N–isopropylacrylamide bearing pH-responsive polymeric micelles and
liposomes as a delivery system for the photosensitizer aluminum chloride phthalocyanine (AlClPc), which was evaluated in photodynamic therapy. pH-responsive polymeric micelles loaded with AlClPc were found to exhibit
increased cytotoxicity against EMT-6 mouse mammary cells in vitro. Liu et al (2003) synthesized cholesteryl end-capped thermally responsive amphiphilic polymers with two different hydrophobic/hydrophilic chain-length
ratios from the hydroxyl-terminated random poly (N–isopropylacrylamide–co–N, N–dimethylacrylamide) and cholesteryl chloroformate. The micellar nanoparticles prepared from the amphiphilic polymers demonstrated
temperature sensitivity. It was suggested that these nanoparticles would make an interesting drug delivery system. Nostrum (2004) reviewed the results of photosensitizers for photodynamic therapy including drug
loading, biodistribution studies, and therapeutic efficiency and concluded that pH-sensitive micelles appeared to be promising candidates for photosensitizer delivery.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
3.1.Micelles
Micelles are ideal bioactive nanocarriers, especially for water insoluble agents. Many amphiphilic block copolymers can be used for this purpose. Polymers can self-associate to form spherical micelles in aqueous solution by keeping hydrophilic ends as the outer shell and the hydrophobic ends as the core. Hydrophobic drugs can be entrapped in the core during micelle formation process. Polymeric micelles have good thermodynamic stability in
physiological solutions, as indicated by their low critical micellar concentration, which makes them stable and prevents their rapid dissociation in vivo. The sizes of micelles are generally less than 100 nm in diameter. This provides them with long-term circulation in blood stream and enhanced endothelial cell ermeability in the vicinity of solid tumors by passive diffusion. If site-specific ligands or antibodies are conjugated to the surface of the micelles, the drug targeted delivery potential of polymeric micelles can be enhanced.Kataoka et al (2000) studied the effective targeting of cytotoxic agents to solid tumors by polymeric micelles. They conjugated doxorubicin to poly(ethylene glycol)-poly( , -aspartic acid) block copolymers and showed that these micelles achieved prolonged circulation in the blood compartment and accumulated more in
the solid tumor, leading to complete tumor regression against mouse C26 tumor. Rapoport (1999) studied stabilization and activation of Pluronic micelles for tumor- targeted drug delivery. Aliabadi et al (2005a) examined
the potential of polymeric micelles to modify the pharmacokinetics and tissue distribution of cyclosporine A (CsA). Their results demonstrated that PEO-b-PCL micelles can effectively solubilize CsA confining CsA to the blood circulation and restricting its access to tissues such as kidney, perhaps limiting the onset of toxicity. They also investigated micelles of methoxy poly (ethylene oxide)–b–poly ( –caprolactone) (PEO–b–PCL) as alternative vehicles for the solubilization and delivery of Cyclosporine A (Aliabadi et al 2005b). They concluded that these nanoscopic PEO–b–PCL micelles have high potential as drug carriers for efficient solubilization and controlled delivery of CsA. Prompruk et al (2005) synthesized a functionalized copolymer with three polymeric components,poly (ethylene glycol)–block–poly (aspartic acid–stat- phenylalanine) and investigated its potential to form micelles via ionic interactions with diminazene aceturate as a model water-soluble drug.Wasylewska et al (2004) entrapped human prostatic acid phosphatase (PAP)entrapped in AOT–isooctane–water reverse micelles and studied the kinetics of1–naphthyl phosphate and phenyl phosphate hydrolysis, catalyzed by PAP. Wang et al (2004) prepared polymeric micelles from poly (ethylene glycol)–distearoyl phosphoethanolamine conjugates (PEG–DSPE) loaded with
Vitamin K3 (VK3) and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). These micelles were stable for 6 months during storage at 4°C and no change in their size or release of the incorporated drugs were observed. They showed that these loaded micelles resulted in synergistic anticancer effects against both murine and human cancer cells in vitro. Kang et al (2004) prepared A-B-A triblock and star-block amphiphilic copolymers such as poly (N–(2–hydroxypropyl) methacrylamide)–block–poly (D,L–lactide)–block–poly (N–(2–hydroxy propyl) methacrylamide), poly (N–vinyl-2–pyrrolidone)–block–poly (D,L–lactide)–block–poly (N–vinyl–2–pyrrolidone), star–poly (D,L–lactide)–block–poly
(N–(2–hydroxypropyl) methacryl amide) and star–poly (D,L–lactide)–block–poly (N–vinylpyrrolidone). They reported that all copolymers self-assembled in aqueous solution to form supramolecular aggregates of 20–180 nm in size. The prepared triblock copolymer micelles were examined as carriers for two drugs, indomethacin and paclitaxel, which are poorly water- soluble. Carrillo and Kane (2004) studied the formation and characterization of self– assembled nanoparticles of controlled sizes based on amphiphilic block copolymers synthesized by ring-opening metathesis polymerization. They showed that the monomer undergoes living polymerization and forms assembled nanoparticles of controlled size. The obtained micelles were fairly monodisperse with dimensions of 30–80 nm depending on the composition of the block polymer.Synthetic copolymers containing phosphorylcholine structure can also be used in the formation of micelles. Phosphorylcholine-based polymers mimic the surface of natural phospholipid membrane bilayers and therefore
demonstrate good biocom- patability. Salvage et al (2005) copolymerised 2-methacryloyloxyethyl phospho- rylcholine (MPC) with two pH responsive comonomers, 2–(diethylamino) ethyl methacrylate (DEA) and 2–
(diisopropyl amino) ethyl methacrylate (DPA), in order to develop pH responsive biocompatible drug delivery vehicles. Koo et al (2005) studied sterically stabilized micelles (SSM) and evaluated camptothecin- containing SSM CPT–SSM) as a new nanomedicine for parenteral administration where camptothecin is a well-established topoisomerase I inhibitor against a broad spectrum of cancers. Konno et al (2001) have shown that 2-ethacryloyloxyethyl phosphorylcholine (MPC) polymer immobilized on poly (l–lactic acid) nanopar- ticles effectively suppressed any unfavourable interactions with biocomponents and improved the blood compatibility of the nanoparticles. It has been suggested that the nanoparticles immobilized with the MPC polymer have the potential use as long–circulating micelles and are good candidates for carrying drugs and diagnostic reagents which can come in contact with blood components. Nishiyama et al (2005) published a review article about
construction and characteristic behaviors of intracellular environment-sensitive micelles that selectively exert drug activity and gene expression in live cells. Xiong et al (2005) grafted poly (lactic acid) to both ends of
Pluronic F87 block copolymer (PEO–PPO–PEO) to obtain amphiphilic P(LA-b-EO-b-PO-b-EO-b-LA) block copolymers. Various types of particles consisting of small micelles were obtained due to the complex structure of the copolymers and a constant initial release rates were observed for procain hydrochloride. Sot and coworkers (2005) investigated the behaviour of N–hexadecanoyl sphingosine (Cer16), N–hexanoylsphingosine (Cer6) and N–acetyl sphingosine (Cer2) ceramides in aqueous media and in lipid-water systems. Cer16 behaved as an insoluble non-swelling amphiphile while both Cer6 and Cer2 behaved as soluble amphiphiles in aqueous solutions. They observed micelle formations for Cer6 and Cer2 at high concentrations as well as phospholipid monolayer formation when the air-water interface is occupied by a phospholipid.Responsivity can be added to micelles by combining pH or temperature sensitive functional groups into the structures. Cammas et al (1997) prepared thermo- responsive polymeric micelles from amphiphilic block copolymers composed of N–isopropylacrylamide as a thermo-responsive outer shell and styrene as hydrophobic inner core. Leroux et al (2001) studied N–isopropylacrylamide bearing pH-responsive polymeric micelles and
liposomes as a delivery system for the photosensitizer aluminum chloride phthalocyanine (AlClPc), which was evaluated in photodynamic therapy. pH-responsive polymeric micelles loaded with AlClPc were found to exhibit
increased cytotoxicity against EMT-6 mouse mammary cells in vitro. Liu et al (2003) synthesized cholesteryl end-capped thermally responsive amphiphilic polymers with two different hydrophobic/hydrophilic chain-length
ratios from the hydroxyl-terminated random poly (N–isopropylacrylamide–co–N, N–dimethylacrylamide) and cholesteryl chloroformate. The micellar nanoparticles prepared from the amphiphilic polymers demonstrated
temperature sensitivity. It was suggested that these nanoparticles would make an interesting drug delivery system. Nostrum (2004) reviewed the results of photosensitizers for photodynamic therapy including drug
loading, biodistribution studies, and therapeutic efficiency and concluded that pH-sensitive micelles appeared to be promising candidates for photosensitizer delivery.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
MICRO AND NANO SYSTEMS(4)
3.MICRO AND NANO DRUG DELIVERY SYSTEMS
One of the most attractive areas of micro and nano research is drug delivery. This includes the design of micro and nano carriers, synthesis of nanomedicines and production of nanosystems that are able to deliver therapeutic drugs to the specific organs or tissues in the body for appropriate periods. For drug delivery vehicles it is very important that these systems have good blood and biocompatibility properties. They themselves or the degradation products should not have any toxic, allergic or inflammatory effects. The systems should also protect the activity of the drugs and improve their transport through the biological barriers. If some specific functionality is added on the system, it would also be possible to deliver the drug to the target site where the system is
stimulated by an appropriate signal.In the design and formulation of delivery systems, the key parameters are the size of the device, entrapment method, stability of drug, degradation parameters of the matrix and release kinetics of drugs. Nanosystems have many advantages over the micro systems such as circulation in blood stream for longer periods without being recognized by macrophages, ease of penetration into tissues through capillaries and biological membranes, ability to be taken up by cells easily, demonstrating high therapeutic activity at the target site, and sustaining the effect at the desired area over a period of days or even weeks. In the last decades, numerous publications came up to describe the design of delivery systems with novel preparation methods, physicochemical properties, and bioactivities.Drug delivery is an interdisciplinary area of research that aims to make the administration of complex drugs feasible. Over the recent years there has been an increasing interest in developing new delivery systems by collaborative research of basic scientists, engineers, pharmacologists, physicians and other health related scientists. The main purpose is to deliver the drug to the desired tissue in the biological system so that it would achieve higher activity for prolonged period at the site without risk of side effects. Micro and nano drug delivery systems are developed for these purposes especially to target the drugs to a specific area or organ in a more stable and reproducible controlled way.Entrapment or conjugation of a drug to a polymeric system may protect the drug from inactivation and help to store its activity for prolonged durations, decrease its toxicity, as well as may achieve administration flexibility.
Various delivery systems, such as emulsions, liposomes, micro and anoparticles, are of major interest in the field of biomedicine and pharmaceutics. Generally biodegradable and bioabsorbable matrices are preferred so that they
would degrade inside the body by hydrolysis or by enzymatic reactions and does not require a surgical operation for removal.Targeted delivery can be achieved by either active or passive targeting. Active targeting of a therapeutic agent is
achieved by conjugating the therapeutic agent or the carrier system to a tissue or cell-specific ligand. Passive targeting is achieved by coupling the therapeutic agent to a macromolecule that passively reaches the target organ. Muvaffak et al (2002, 2004a, 2004b, 2005) prepared anticancer drug- containing gelatin microspheres and conjugated antibodies on the surfaces of these biodegradable microspheres. It was reported that the systems prepared in this way demonstrated specific activity towards its antigen. Monsigny et al (1994) reviewed the main properties of neoglycoproteins and glycosylated polymers which have been developed to study the properties of endogenous lectins and to carry drugs which can form specific ligands with cell surface receptors. The glycocon- jugates have been successfully used to carry biological response modifiers such as N-acetylmuramyldipeptide which is hundreds of times more efficient in rendering macrophages tumoricidal when it is bound to this type of
carriers. Complexes of polycationic glycosylated polymers with plasmid DNA molecules are also very efficient in transfecting cells in a sugar-dependent manner.Bioactive agents can be incorporated in micro and nano systems or in systems which have microporous structures. Local delivery of drugs or growth factors which are embedded in microporous gelatin structures was
reported by Ulubayram and coworkers (2001, 2002). They examined release kinetics of bovine serum albumin proteins from gelatin matrices (Ulubayram et al 2002) and also reported fast and proper healing of full skin defects on rabbits with application of gelatin sponges loaded with epidermal growth factor (EGF) (Ulubayram et al 2001). EGF was added in gelatin microspheres which were crosslinked with various amounts of crosslinkers (Ulubayram et al 2001, 2002). Similar systems were studied by Sakallioglu and colleagues (2002, 2004) and
positive effects of low-dose EGF loaded gelatin microspheres in colonic anastomosis were reported. Uguralp et al (2004) also reported positive effects of sustained and local administration of EGF incorporated to biodegradable
membranes on the healing of bilateral testicular tissue after torsion. Guler et al (2004) examined the effects of locally applied fibroblast containing microporous gelatin sponges on the testicular morphology and blood flow in
rats.There are a large number of studies investigating the drug releasing responses to various stimuli such as pH, temperature, electric field, ultrasound, light, or other stresses. Kim et al (2000) prepared nanospheres with core-
shell structure from amphiphilic block copolymers by using PEO-PPO-PEO block copolymer (Pluronic) and poly(-caprolactone). Release behaviors of indomethacin from Pluronic/PCL block copolymeric nanospheres showed
temperature dependence and a sustained release pattern. Chilkoti et al (2002) described recursive directional ligation approach to synthesis of recombinant polypeptide carriers for the targeted delivery of radionuclides,
chemotherapeutics and biomolecular therapeutics to tumors by using a thermally responsive, elastin-like polypeptide as the drug carrier. Determan et al (2005) synthesized a family of amphiphilic ABCBA pentablock
copolymers based on the commercially available Pluronic® F127 block copolymers and various amine containing methacrylate monomers. The systems exhibited both temperature and pH responsiveness. They suggested that
the copolymers have high potential for applications in controlled drug delivery and non-viral gene therapy due to their tunable phase behavior and biocompatibility. Micro and nano systems for drug delivery applications can be
studied in the classes of micelles, liposomes, dendrimers, and particles of polymeric and ceramic materials as explained in the following sections.
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
One of the most attractive areas of micro and nano research is drug delivery. This includes the design of micro and nano carriers, synthesis of nanomedicines and production of nanosystems that are able to deliver therapeutic drugs to the specific organs or tissues in the body for appropriate periods. For drug delivery vehicles it is very important that these systems have good blood and biocompatibility properties. They themselves or the degradation products should not have any toxic, allergic or inflammatory effects. The systems should also protect the activity of the drugs and improve their transport through the biological barriers. If some specific functionality is added on the system, it would also be possible to deliver the drug to the target site where the system is
stimulated by an appropriate signal.In the design and formulation of delivery systems, the key parameters are the size of the device, entrapment method, stability of drug, degradation parameters of the matrix and release kinetics of drugs. Nanosystems have many advantages over the micro systems such as circulation in blood stream for longer periods without being recognized by macrophages, ease of penetration into tissues through capillaries and biological membranes, ability to be taken up by cells easily, demonstrating high therapeutic activity at the target site, and sustaining the effect at the desired area over a period of days or even weeks. In the last decades, numerous publications came up to describe the design of delivery systems with novel preparation methods, physicochemical properties, and bioactivities.Drug delivery is an interdisciplinary area of research that aims to make the administration of complex drugs feasible. Over the recent years there has been an increasing interest in developing new delivery systems by collaborative research of basic scientists, engineers, pharmacologists, physicians and other health related scientists. The main purpose is to deliver the drug to the desired tissue in the biological system so that it would achieve higher activity for prolonged period at the site without risk of side effects. Micro and nano drug delivery systems are developed for these purposes especially to target the drugs to a specific area or organ in a more stable and reproducible controlled way.Entrapment or conjugation of a drug to a polymeric system may protect the drug from inactivation and help to store its activity for prolonged durations, decrease its toxicity, as well as may achieve administration flexibility.
Various delivery systems, such as emulsions, liposomes, micro and anoparticles, are of major interest in the field of biomedicine and pharmaceutics. Generally biodegradable and bioabsorbable matrices are preferred so that they
would degrade inside the body by hydrolysis or by enzymatic reactions and does not require a surgical operation for removal.Targeted delivery can be achieved by either active or passive targeting. Active targeting of a therapeutic agent is
achieved by conjugating the therapeutic agent or the carrier system to a tissue or cell-specific ligand. Passive targeting is achieved by coupling the therapeutic agent to a macromolecule that passively reaches the target organ. Muvaffak et al (2002, 2004a, 2004b, 2005) prepared anticancer drug- containing gelatin microspheres and conjugated antibodies on the surfaces of these biodegradable microspheres. It was reported that the systems prepared in this way demonstrated specific activity towards its antigen. Monsigny et al (1994) reviewed the main properties of neoglycoproteins and glycosylated polymers which have been developed to study the properties of endogenous lectins and to carry drugs which can form specific ligands with cell surface receptors. The glycocon- jugates have been successfully used to carry biological response modifiers such as N-acetylmuramyldipeptide which is hundreds of times more efficient in rendering macrophages tumoricidal when it is bound to this type of
carriers. Complexes of polycationic glycosylated polymers with plasmid DNA molecules are also very efficient in transfecting cells in a sugar-dependent manner.Bioactive agents can be incorporated in micro and nano systems or in systems which have microporous structures. Local delivery of drugs or growth factors which are embedded in microporous gelatin structures was
reported by Ulubayram and coworkers (2001, 2002). They examined release kinetics of bovine serum albumin proteins from gelatin matrices (Ulubayram et al 2002) and also reported fast and proper healing of full skin defects on rabbits with application of gelatin sponges loaded with epidermal growth factor (EGF) (Ulubayram et al 2001). EGF was added in gelatin microspheres which were crosslinked with various amounts of crosslinkers (Ulubayram et al 2001, 2002). Similar systems were studied by Sakallioglu and colleagues (2002, 2004) and
positive effects of low-dose EGF loaded gelatin microspheres in colonic anastomosis were reported. Uguralp et al (2004) also reported positive effects of sustained and local administration of EGF incorporated to biodegradable
membranes on the healing of bilateral testicular tissue after torsion. Guler et al (2004) examined the effects of locally applied fibroblast containing microporous gelatin sponges on the testicular morphology and blood flow in
rats.There are a large number of studies investigating the drug releasing responses to various stimuli such as pH, temperature, electric field, ultrasound, light, or other stresses. Kim et al (2000) prepared nanospheres with core-
shell structure from amphiphilic block copolymers by using PEO-PPO-PEO block copolymer (Pluronic) and poly(-caprolactone). Release behaviors of indomethacin from Pluronic/PCL block copolymeric nanospheres showed
temperature dependence and a sustained release pattern. Chilkoti et al (2002) described recursive directional ligation approach to synthesis of recombinant polypeptide carriers for the targeted delivery of radionuclides,
chemotherapeutics and biomolecular therapeutics to tumors by using a thermally responsive, elastin-like polypeptide as the drug carrier. Determan et al (2005) synthesized a family of amphiphilic ABCBA pentablock
copolymers based on the commercially available Pluronic® F127 block copolymers and various amine containing methacrylate monomers. The systems exhibited both temperature and pH responsiveness. They suggested that
the copolymers have high potential for applications in controlled drug delivery and non-viral gene therapy due to their tunable phase behavior and biocompatibility. Micro and nano systems for drug delivery applications can be
studied in the classes of micelles, liposomes, dendrimers, and particles of polymeric and ceramic materials as explained in the following sections.
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
MICRO AND NANO SYSTEMS(3)
2.MICRO AND NANO TECHNOLOGY IN MEDICINE
Micro and nanotechnology have significant applications in the biomedical area, such as drug delivery, gene therapy, novel drug synthesis, imaging, etc. In diagnostics and treatment of many disorders, micro-electro-mechanical systems (MEMS) and biocompatible electronic devices have great potentials. MEMS are formed by integration of mechanical elements, sensors, actuators and electronics on a common silicon wafer with microelectronics and micromachining technologies. Sensors collect information from the environment by measuring mechanical, thermal, biological, chemical, optical or magnetic parameters; electronics process these information and actuators respond by moving, positioning, regulating, pumping or filtering. Therefore a desired response occurs against the stresses and environment is controlled by the system.Use of nano devices in imaging is another important area especially in the detection of tumor cells. In principle, nanoparticles injected into the body detect cancer cells and bind to them. They behave as contrast agents making
the malignant area visible so that the anatomical contours of the cancer lesion can be defined. For this purpose iron- oxide nanoparticles whose surfaces were modified by amines were prepared by Shieh et al (2005) and a fast and prolonged inverse contrast effect was shown in the liver in vivo that lasted for more than 1 week. Medical applications of metallic nanoparticles were studied by different groups. For example Dua et al (2005) constructed a non- toxic, biomimetic interface for immobilization of living cells by mixing colloidal gold nanoparticles in carbon paste and studied its electrochemical exogenous effect on cell viability. Pal et al (2005) prepared gold nanoparticles in the presence of a biopolymer, sodium alginate by UV photoactivation. Carrara et al (2005)
prepared nanocom- posite materials of poly(o-anisidine) containing titanium dioxide nanoparticles, carbon black and multi-walled carbon nanotubes for biosensor applications. The synthe- sized materials were deposited in thin
films in order to investigate their impedance characteristics. Lee et al (2005) prepared ultrafine poly(acrylonitrile) (PAN) fibers containing silver nanoparticles. Silver ions in a PAN solution were reduced to produce Ag
nanoparticles and the resulting solution was electrospun into ultrafine PAN fibers. Morishita et al (2005) associated HVJ-E (hemagglutinating virus of Japan- envelope) with magnetic nanoparticles so that they can
potentially enhance its transfection efficiency in the presence of a magnetic force. It was reported that, heparin coated maghemite nano particles enhanced the transfection efficiency in the analysis of direct injection into the
mouse liver. They proposed that the systemcould potentially help overcome fundamental limitations to gene therapy in vivo.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
Micro and nanotechnology have significant applications in the biomedical area, such as drug delivery, gene therapy, novel drug synthesis, imaging, etc. In diagnostics and treatment of many disorders, micro-electro-mechanical systems (MEMS) and biocompatible electronic devices have great potentials. MEMS are formed by integration of mechanical elements, sensors, actuators and electronics on a common silicon wafer with microelectronics and micromachining technologies. Sensors collect information from the environment by measuring mechanical, thermal, biological, chemical, optical or magnetic parameters; electronics process these information and actuators respond by moving, positioning, regulating, pumping or filtering. Therefore a desired response occurs against the stresses and environment is controlled by the system.Use of nano devices in imaging is another important area especially in the detection of tumor cells. In principle, nanoparticles injected into the body detect cancer cells and bind to them. They behave as contrast agents making
the malignant area visible so that the anatomical contours of the cancer lesion can be defined. For this purpose iron- oxide nanoparticles whose surfaces were modified by amines were prepared by Shieh et al (2005) and a fast and prolonged inverse contrast effect was shown in the liver in vivo that lasted for more than 1 week. Medical applications of metallic nanoparticles were studied by different groups. For example Dua et al (2005) constructed a non- toxic, biomimetic interface for immobilization of living cells by mixing colloidal gold nanoparticles in carbon paste and studied its electrochemical exogenous effect on cell viability. Pal et al (2005) prepared gold nanoparticles in the presence of a biopolymer, sodium alginate by UV photoactivation. Carrara et al (2005)
prepared nanocom- posite materials of poly(o-anisidine) containing titanium dioxide nanoparticles, carbon black and multi-walled carbon nanotubes for biosensor applications. The synthe- sized materials were deposited in thin
films in order to investigate their impedance characteristics. Lee et al (2005) prepared ultrafine poly(acrylonitrile) (PAN) fibers containing silver nanoparticles. Silver ions in a PAN solution were reduced to produce Ag
nanoparticles and the resulting solution was electrospun into ultrafine PAN fibers. Morishita et al (2005) associated HVJ-E (hemagglutinating virus of Japan- envelope) with magnetic nanoparticles so that they can
potentially enhance its transfection efficiency in the presence of a magnetic force. It was reported that, heparin coated maghemite nano particles enhanced the transfection efficiency in the analysis of direct injection into the
mouse liver. They proposed that the systemcould potentially help overcome fundamental limitations to gene therapy in vivo.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
MICRO AND NANO SYSTEMS(2)
1.INTRODUCTION
Development of metal, ceramic, polymer or materials of biological origin for use in medicine is a very important research area of the last decades. Scientists made great innovations in the production of artificial organs and tissues such as dental and orthopedic prostheses, artificial veins and heart valves, contact lenses, tissue engineering scaffolds, diagnostic systems, etc. As the knowledge on materials and biological systems improved,new areas such as interaction between the material and cells, effect of therapeutic agents at molecular level, the relation between the molecular structure and macroscopic properties became important research lines. Scientists are increasingly interested in mimicking the biological systems, under- standing cell-cell communications and modeling the structures that already exist in nature. This curiosity makes them search individual molecules, study interac- tions between the functional groups, signaling between the cells at micro and nano levels to be able to
control the properties of the artificial and biological systems. Technologies based on micro and nano levels involve synthesis and utilization of materials, devices and systems in which at least one dimension is less than 1 mm or in the submicron range, respectively.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
Development of metal, ceramic, polymer or materials of biological origin for use in medicine is a very important research area of the last decades. Scientists made great innovations in the production of artificial organs and tissues such as dental and orthopedic prostheses, artificial veins and heart valves, contact lenses, tissue engineering scaffolds, diagnostic systems, etc. As the knowledge on materials and biological systems improved,new areas such as interaction between the material and cells, effect of therapeutic agents at molecular level, the relation between the molecular structure and macroscopic properties became important research lines. Scientists are increasingly interested in mimicking the biological systems, under- standing cell-cell communications and modeling the structures that already exist in nature. This curiosity makes them search individual molecules, study interac- tions between the functional groups, signaling between the cells at micro and nano levels to be able to
control the properties of the artificial and biological systems. Technologies based on micro and nano levels involve synthesis and utilization of materials, devices and systems in which at least one dimension is less than 1 mm or in the submicron range, respectively.
Source:
Nanomaterials and Nanosystems for Biomedical Applications
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
MICRO AND NANO SYSTEMS(1)
MICRO AND NANO SYSTEMS IN BIOMEDICINE AND DRUG DELIVERY
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
Micro and nano sytems sysnthesized from organic and inorganic materials are gaining great attention in biomedical applications such as design of biosensors, construction of imaging systems, synthesis of drug carrying and drug targeting devices, etc. Emulsions, suspensions, micelles, liposomes, dendrimers, polymeric and responsive systems are some examples for drug carrier devices. They have lots of advantages over conven- tional systems since they enhance the delivery, extend the bioactivity of the drug by protecting them from environmental effects in biological media, show minimal side effects, demonstrate high performance characteristics, and are more economical since minimum amount of expensive drugs are used. This chapter provides brief infor- mation about micro and nano systems used in biomedicine, nanobiotechnology and drug delivery
Keywords:micelles, liposomes, dendrimers, drug carriers, responsive polymers
Source:
Nanomaterials and Nanosystems for Biomedical ApplicationsNESRIN HASIRCIMiddle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
NESRIN HASIRCI
Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
Micro and nano sytems sysnthesized from organic and inorganic materials are gaining great attention in biomedical applications such as design of biosensors, construction of imaging systems, synthesis of drug carrying and drug targeting devices, etc. Emulsions, suspensions, micelles, liposomes, dendrimers, polymeric and responsive systems are some examples for drug carrier devices. They have lots of advantages over conven- tional systems since they enhance the delivery, extend the bioactivity of the drug by protecting them from environmental effects in biological media, show minimal side effects, demonstrate high performance characteristics, and are more economical since minimum amount of expensive drugs are used. This chapter provides brief infor- mation about micro and nano systems used in biomedicine, nanobiotechnology and drug delivery
Keywords:micelles, liposomes, dendrimers, drug carriers, responsive polymers
Source:
Nanomaterials and Nanosystems for Biomedical ApplicationsNESRIN HASIRCIMiddle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Ankara 06531, Turkey
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