dlpla polyllactide pga polyglycolide dlplga polydllactidecoglycolide pcl poly �caprolactone table selected examples of block copolymers for production of biodegradable nanospheres plapolyethyleneglycol, plapeg monomethoxypegpolyalkylcyanoacrylate polypolyethyleneglycolcyanoacrylatecohexadecylcyanoacrylate polyethyleneoxidebsebacic acid polyphosphazenepolyethyleneoxide polymethyloxazolinebpolydimethylsiloxanebpolymethyloxazoline or by polymerization of monomers commonly used methodologies include the solvent cephalexin keflex 500 mg evaporation, the spontaneous emulsificationsolvent diffusion, nanoprecipitation or solvent displacement and emulsion polymerization techniques the method of choice depends on the polymer and the drug type, as well as the required particle size distribution and polydispersity indices however, some polymers, such cephalexin keflex 500 mg as comblike polyesters, the diblock copolymer polyethylene oxidebsebacic acid and triblock copolymer poly methyloxazolinebpolydimethylsiloxanebpolymethyloxazoline can spontaneously form stable nanoparticles coreshell type nanospheres in the solvent evaporation method, the polymer is simply dissolved together with the drug in an organic solvent cephalexin keflex 500 mg and the mixture is then emulsified to form either an oilinwater nanoemulsion for encapsulation of hydrophobic drugs or water inoil nanoemulsion for encapsulation of hydrophilic drugs using suitable surfactants nanoparticles are then obtained following evaporation of the solvent and can cephalexin keflex 500 mg be concentrated by filtration, centrifugation or lyophilization the spontaneous emulsificationsolvent diffusion method is a modified version of the solvent evaporation technique, which utilizes a watersoluble solvent eg methanol or acetone along with a waterinsoluble one such as chloroform as a cephalexin keflex 500 mg result of the spontaneous diffusion of the watersoluble solvent into the waterinsoluble phase, an interfacial turbulence is created leading to the formation of nanoparticles nanoprecipitation, however, is a versatile and simple method this is based on spontaneous formation of nanoparticles cephalexin keflex 500 mg during phase separation the marangoni effect, which is induced by slow addition of the diffusing phase polymerdrug solution to the dispersing phase a nonsolvent of the polymers, which is miscible with the solvent that sol ubilizes the polymer the dispersing cephalexin keflex 500 mg phase may contain surfactants depending on the solvent choice and solventnonsolvent volume ratio, this method is suitable for encapsulation of both watersoluble and hydrophobic drugs, as well as proteinbased pharmaceuticals in emulsion polymerization, the monomer is dispersed into an aqueous phase cephalexin keflex 500 mg using an emulsifying agent the initiator radicals are generated in the aqueous phase and they diffuse into the monomerswollen micelles anionic polymerization in the micelles is then initiated by the hydroxyl ions of water chain transfer agents are abundant and termination occurs by radical combination the size and molecular masses of nanoparticles are dependent on the initial ph of the polymerization medium drugs are incorporated during the polymerization step or can be adsorbed into the nanosphere surface afterwards the addition cephalexin keflex 500 mg of cyclodextrins to the polymerization medium can promote the encapsulation of poorly water soluble drugs depending on the monomer used, some drugs can also initiate the polymerization step, resulting in the covalent attachment of drug molecules to the nanospheres for cephalexin keflex 500 mg instance, photosensitizers such as naphthalocyanines, can initiate the polymerization of alkylcyanoacrylates a number of specialized approaches eg dialysis, saltingout, supercritical fluid technology, denaturation, ionic interaction, ionic gelation, and interfacial polymerization have also been described for the preparation of polymeric nanoparticles, based on the choice of the starting material and the biological needs drug release mechanisms the release profile of drugs from nanoparticles depends on the physicochemical nature of the drug molecules as well as the matrix �, factors include mode of drug attachment andor encapsulation eg surface adsorption, dispersion homogeneity of drug molecules in the polymer matrix, covalent conjugation, the physical state of the drug within the matrix such as crystal form, and parameters controlling matrix hydration andor degradation generally, cephalexin keflex 500 mg rapid release occurs by desorp tion, where the drug is weakly bound to the nanosphere surface if the drug is uniformly distributed in the polymer matrix, the release occurs either by diffusion if the encapsulated drug is in crystalline form, cephalexin keflex 500 mg the drug is first dissolved locally and then diffuses out or erosion of the matrix, or a combination of both mechanisms erosion can be further subdivided into either homogeneous with uniform degradation rates throughout the matrix or heterogeneous where degradation is cephalexin keflex 500 mg confined at the surface processes parameters such as polymer molecular weight distribution, crystallinity, hydrophobicityhydrophilicity, melting and glass transition temperature, polymer blends and prior polymer treatment eg oxygenplasma treatment all control the extent of matrix hydration and degradation for instance, in cephalexin keflex 500 mg the case of aliphatic polyesters, their degradation time is shorter for low molecular weight polymers, more hydrophilic polymers, more amorphous polymers and copolymers with high glycolide content table sitespecific targeting with nanoparticles importance of size and surface properties numerous articles cephalexin keflex 500 mg have recently discussed the importance of nanoparticle size and surface characteristics in controlling their biodistribution, following different routes of administration only a brief overview is provided here following intravenous injection, liver kupffer cells and spleen marginal zone and red pulp cephalexin keflex 500 mg macrophages clear polymeric nanoparticles rapidly from the blood circulation opsonization, which is surface deposition of blood opsonic factors such as fibronectin, immunoglobulins, creactive and certain complement proteins, often aid particle recognition by these macrophages indeed, the propensity of macrophages of cephalexin keflex 500 mg the reticuloendothelial system for rapid recognition and clearance of particulate matter has provided a rational approach to macrophage specific targeting with nanoparticles eg for the treatment of obligate intracellular microorganisms, delivery of toxins for macrophage killing, and diagnostic agents however, cephalexin keflex 500 mg the rapid sequestration of nanoparticles by macrophages in contact with blood is problematic for the efficient targeting of polymeric nanoparticles to non macrophage sites thus, inherent in nanoparticle design is the precision surface manipulation and engineering with synthetic polymers this affords control over nanoparticle interaction and fate within biological systems there are numerous examples where the surface of nanocarriers is carefully assembled with projected macromolecular hairs made from polyethyleneglycol, peg, or its derivatives eg methoxypegalbumin, plapeg or other related polymers cephalexin keflex 500 mg [eg block copolymers such as selected poloxamers and poloxamines, polyphosphazene polyethyleneoxide], this is achieved either during the particle assembly procedures or polymerization step, or post particle manufacturing this strategy suppresses macrophage recognition by an array of complex mechanisms, which collectively achieve cephalexin keflex 500 mg reduced protein adsorption and surface opsonization therefore, such entities, provided that they are below nm in size, exhibit prolonged residency time in the circulation, and are referred to as stealth or macrophage evading nanoparticles, the efficiency of the macrophageevading process cephalexin keflex 500 mg is dependent on polymer type and its surface stability, reactivity, and physics eg surface density and assumed conformation prolonged circulation properties are ideal for slow or controlled release of therapeutic agents in the blood to treat vascular disorders long circulating cephalexin keflex 500 mg polymeric nanoparticles may have application in vascular imaging too eg detection of vascular bleeding or abnormalities longcirculating nanoparticles can also escape from vasculature and this is normally restricted to sites where the capillaries have open fenestration or when the integrity cephalexin keflex 500 mg of the endothelial barrier is perturbed by inflammatory processes or by tumor growth however, extravasated nanoparticles, as in tumour interstitium, distribute heterogeneously in perivascular clusters that do not move significantly these particles may therefore act as depot systems, particularly for cephalexin keflex 500 mg the sustained release of antiangiogenic agents, and to some extent, for drug delivery to multidrug resistant tumors eg by coencapsulation of both anticancer drugs and the competitive inhibitors of active drug efflux pumps the surface of longcirculating nanoparticles is also cephalexin keflex 500 mg amenable for modification with targeting ligands such entities can navigate capillaries and escape routes in search of signature molecules expressed by the target this process is often referred to as active targeting for example, certain cancer cells express folate receptors cephalexin keflex 500 mg and these receptors have the ability to endocytose stealth nanoparticles that are decorated with folic acid delivery of anticancer agents to tumor cells by such means could overcome the possibility of multidrug resistance nondeformable stealth nanoparticles, however, are prone to splenic cephalexin keflex 500 mg filtration at interendothelial cell slits, if their size exceeds that of the width of the cell slits nm indeed, these splenotropic vehicles can deliver their cargo efficiently to the redpulp regions of the sinusoidal spleen activated or stimulated macrophages are cephalexin keflex 500 mg also known to rapidly phagocytose stealth nanoparticles stealth nanospheres may therefore have applications as diagnosticimaging tools for the identification of stimulated or newly recruited hepatic macrophages such diagnostic procedures may prove useful for patient selection or for monitoring the progress cephalexin keflex 500 mg of treatment with longcirculating nanoparticles carrying anticancer agents, thus minimizing damage to hepatic macrophages polymeric nanospheres can also target endothelial cells on the blood brain barrier for instance, following intravenous injection polysorbate coated polyalkylcyanoacrylate, ����, nanospheres attract apolipoprotein e from cephalexin keflex 500 mg the blood, thus mimicking low density lipoprotein ldl and become recognizable by ldl receptors expressed by the bloodbrain barrier endothelial cells another related example is pegcoated ���� nanoparticles, with the ability to localize mainly in the ependymal cells of the cephalexin keflex 500 mg choroid plexus and the epithelial cells of pia region and the ventricles of the mouse and the rat brain the molecular basis of this deposition pattern remains to be unravelled others have administered nanoparticles directly to pathological sites for optimal biological performance one example is intramurally delivered plga nanoparticles to an injured artery following angioplasty, using a cardiac infusion catheter here, nanoparticles penetrate the dilated arterial wall under pressure and once the pressure is released, the artery returns to its cephalexin keflex 500 mg normal state resulting in particle immobilization in the arterial wall, where they may act as a sustained release system for drugs and genetic materials again, particle size is an important parameter the smaller the size, the greater the arterial deposition and cellular entry, as well as lower inflammatory responses polymeric nanospheres also provide intriguing opportunities for lymphatic drug delivery, as well as for diagnostic imaging of the lymphatic vessels and their associated lymph nodes when injected interstitially the extent of lymphatic cephalexin keflex 500 mg delivery and lymph node localization of nanospheres depends on their size and surface characteristics for instance, hydrophilic nanoparticles, in the size range of nm, as opposed to their hydrophobic counterparts, repulse each other and interact poorly with the ground substance cephalexin keflex 500 mg of the interstitium and drain rapidly into the initial lymphatics through patent junctions in the lymphatic capillaries, the drained particles are conveyed to the nodes via the afferent lymph macrophages of medullary sinuses and paracortex are mainly responsible for particle cephalexin keflex 500 mg capture from the lymph, but this also depends on nanoparticle surface properties larger nanospheres nm, however, are retained at interstitial sites for prolonged periods of time and may therefore act as sustained release systems for drugs and antigens , for example, cephalexin keflex 500 mg largesized plga particles can provide antigen release over weeks and months following continuous or pulsatile kinetics by mixing particle types with different degradation and pulsatile release kinetics, multiple discrete booster doses of encapsulated antigens can be provided after a single cephalexin keflex 500 mg administration of the formulation eg and months an alternative approach is the use of nanoparticle hydrogels for slow and local antigen release for example, by controlling the ionic strength of the dispersion medium, monodisperse nanoparticles of polyhydroxyethylmethacrylate, polyhema, and poly[hemacomethacrylic cephalexin keflex 500 mg acid] coalesce together to form a shape retentive hydrogel suitable for interstitial implantation macromolecules may be trapped between the particle aggregates and their release is controlled by a combination of diffusion larger particles packed together have larger spaces in the cephalexin keflex 500 mg lattice, and this allows for faster diffusion and erosion arising from aggregates that contain particles with methacrylic acid nanoparticles that erode from the aggregate are drained into the lymphatic system and may be retained by the regional nodes similarly, by cephalexin keflex 500 mg controlling the inherent physical attractive forces between model polystyrene nanoparticles, ordered lattices fig scanning electron micrographs of uncoated and surfacemodified polystyrene nanoparticles due to surface hydrophobicity uncoated nanospheres a, nm in size, tend to aggregate by controlling the physical attractive forces cephalexin keflex 500 mg between the nanoparticles by surface coating with an appropriate concentration of a block copolymer, ordered structures are formed and these can be deposited onto the surface of large microspheres b can be deposited on the surface of very large microspheres cephalexin keflex 500 mg fig following subcutaneous localization, surface adsorbed nanospheres may gradually detach from the parent microsphere and gain entry into the lumen of the lymphatic capillaries polymeric nanoparticles also have numerous applications following oral delivery evidence suggests that the adsorption of particulates in the intestine following oral administration take place at the peyers patches the epithelial cell layer overlying the peyers patches contains specialized m cells these cells can sample particles from the lumen and transport them to the underlying macrophages and cephalexin keflex 500 mg dendritic cells indeed, numerous studies have confirmed protective immunity induced by mucosal immunization with ����, plga and chitosan based particulate systems part of the success is due to the encapsulation of antigens in polymeric particulate systems, which provides better protection cephalexin keflex 500 mg for the antigen during intestinal transit the immune outcomes have included mucosal secretory iga and serum antibody igg and igm responses, as well as systemic cytotoxic t lymphocyte responses in splenocytes induction of an appropriate immune response following oral administration cephalexin keflex 500 mg depends primarily on factors that affect uptake and particle translocation by m cells these include particle size, dose, composition, and surface chemistry, as well as the region of the intestine where particles are taken up, membrane recycling from intracellular sources and the species tolerance to orally administered microparticulate encapsulated antigens is another potential outcome, but it has received little attention the bioavailability of some drugs can be improved after oral administration by means of polymeric nanoparticles this is a reflection of cephalexin keflex 500 mg drug protection by the nanoparticle against hostile conditions of the gastrointestinal tract, as well as the mode of nanoparticle interaction with mucosal layers however, the bioad hesive properties of nanoparticles may vary with their size and surface characteristics eg surface cephalexin keflex 500 mg charge, surface polymer density and conformation, as well as the location and type of the mucosal surface in the gastrointestinal tract similarly, improved drug bioavailability has also been reported following ocular administration with pla, ����, polybutylcyanoacrylate and eudragit nanoparticles for cephalexin keflex 500 mg example, loading of tamoxifen in pegylated nanoparticles proved successful in the treatment of autoimmune uveortinitis following intraocular injection interaction of surfacemodified polymeric nanoparticles with nasal associated lymphoid tissue and their transport across nasal mucosa have also received attention, particularly with cephalexin keflex 500 mg respect to peptidebased pharmaceuticals and antigen delivery conclusions polymeric nanoparticles are promising vehicles for sitespecific and controlled delivery of therapeutic agents, following different routes of administration and these trends seem to continue with advances in materials and polymer chemistry and cephalexin keflex 500 mg pharmaceutical nanotechnology however, nanoparticles do not behave similarly their encapsulation capacity, drug release profile, biodistribution and stability vary with their chemical makeup, morphology and size inherently, nanosphere design and targeting strategies may vary according to physiological and therapeutic needs, as cephalexin keflex 500 mg well as in relation to the type, developmental stage and location of the disease attention should also be paid to toxicity issues that may arise from nanoparticle administration and the release of their polymeric contents and 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