am heart assoc sci sess ibid lundgren ce, bergoe gw and tyssebotn i the theory and application of intravascular microbubbles as an ultraeffective means of transporting oxygen and other gases undersea hyperb med awasthi vd, garcia d, goins ba and phillips wt circulation and biodistribution profiles of longcirculating pegliposomes of various sizes in rabbits int j pharm ibid groneberg da, witt c, wagner u, chung kf and fischer a fundamentals of pulmonary drug delivery respir med nanocapsules preparation, characterization and therapeutic applications ruxandra gref and patrick couvreur introduction over the past decades, the new field of drug delivery has gained more and more attention by scientists, industry specialists and clinical doctors it is now cheap viagra switch maestro recognized that both the inherent value of an active molecule and the delivery system are crucial to achieve the desired pharmacological responses indeed, the administration of some newly developed powerful drug molecules is strongly limited by their inadequate biopharmaceutical profiles moreover, it is sometimes difficult to synthesize new drugs with adequate stability and permeability properties in this case, the drug is unable to reach the adequate biological compartment therefore, the development of appropriate delivery systems for these compounds would be a step forward for their clinical exploitation not only could the entrapment of these drugs in nanoparticles protect them from the biological environment, it also facilitates their transport through biological barriers nanoparticles are generally but not cheap viagra switch maestro necessarily defined as submicronic [xm colloidal systems, made of polymers preferably biodegradable nanoparticles are at least ten times smaller than microparticles zm, which allows them to be administered intravenously without any risk of embolization according to the process and the composition used in the preparation of nanoparticles, nanospheres or nanocapsules can be obtained nanospheres are matrix systems in which the drug is dispersed within the polymer throughout the particle contrarily, nanocapsules are vesicular or reservoir heterogenous systems, in which the drug is essentially confined to a cavity surrounded by a tiny polymeric membrane fig as in the case of nanospheres, depending on their physicochemical properties and composition, the drug may adsorb onto the surface as cheap viagra switch maestro well as being included in the central core of nanocapsules therefore, drug localization is an important parameter in the characterization of nanocapsule preparations the nanocapsule core may be acqueous or composed of a lipophilic solvent, usually an oil in order to achieve good drug loading, the core materials are chosen among the good solvents for the drug expected advantages of confining the drug within a central cavity are a burst effect may be avoided b the drug is not in direct contact with tissues and therefore irritation at the site of administration could be reduced, and c the drug may be better protected from degradation both during storage and after administration one of the advantages of cheap viagra switch maestro nanocapsules over nanospheres is their low polymer content and a high loading capacity for lipophilic drugs fig a schematic representation of the nanocapsule structure b morphological appearance of a nanocapsule with an oily core transmission electron microscopy after freeze fracture i �� nanocapsules can either be obtained by interfacial polymerization of monomers or from preformed polymers in the former, the molar mass of the coating polymer will depend on the preparation conditions and even on the drug used, whereas in the latter, it is determined al the outset polymerization of monomers may lead to a covalent linkage between the polymer and the drug to date, all the methodologies described for preparing nanocapsules involve the preparation cheap viagra switch maestro of emulsions oilinwater ow emulsions lead to the formation of nanocapsules with an oily core, suspended in water waterinoil wo emulsions lead to the obtention of nanocapsules with an acqueous core, suspended in oil more recently, nanocapsules with an acqueous core suspended in an acqueous medium were also obtained nanocapsule technology and their pharmaceutical applications will be further discussed according to the method of obtaining the polymeric wall polymerization in situ or preformed polymer and whether the core is acqueous or oily preparation nanocapsules obtained by interfacial polymerization the advantage of obtaining nanocapsules by interfacial polymerization is that the polymer is formed in situ, allowing the polymer membrane to follow the contours of the inner phase cheap viagra switch maestro of an �w or wo emulsion, thus entrapping drugs with high loadings however, because reactive monomers are used, unwanted chemical reactions may occur between the drug and the monomer, before or during the polymerization process the preparation of nanocapsules by polymerization requires a fast polymerization of the monomers at the interface between the organic and the acqueous phase of the emulsions alkylcyanoacrylates, which polymerize within seconds, have been proposed for the preparation of both oil and watercontaining nanocapsules their polymerization is initiated by hydroxyl ions either from the equilibrium dissociation of water or what is the drug cipro wiki by nucleophilic groups of any compound in the polymerization medium oilcontaining nanocapsules the oilcontaining nanocapsules are suitable for the encapsulation of the cheap viagra switch maestro lipophilic and oilsoluble compounds they are generally obtained by interfacial polymerization of alkylcyanoacrylates, after preparing a very fine oilinwater emulsion with an additional watermiscible organic solvent such as ethanol or acetone these solvents serve as vehicles for the monomers, and also help to disperse the oil as very small droplets in the acqueous phase, which contains a hydrophilic surfactant indeed, as pointed out by gallardo et al, the organic solvents must be completely watermiscible, so that the formation of small enough oil droplets occurs spontaneously, while the solvent is diffusing towards the acqueous phase and the water is diffusing toward the organic phase meanwhile, the polymerization of the monomer induced by the contact with hydroxyl ions cheap viagra switch maestro from the water phase must be swift to allow efficient formation of the polymer envelope around the oil droplet, thus achieving effective encapsulation of drugs generally, particles with sizes ranging between and nm, depending on the experimental conditions, were obtained in a general procedure of nanocapsule preparation, the oil, the monomer, and the biologically active compound are dissolved together in the watermiscible organic solvent to prepare the organic phase this organic phase is then injected via a cannula, under strong stirring, into the acqueous phase containing water and a hydrophilic surfactant the nanocapsules are formed to give a milky suspension immediately the organic phase is then removed under reduced pressure and the nanocapsules are purified cheap viagra switch maestro by ultracentrifugation depending on the density of the oil forming the core, nanocapsules will concentrate either as a pellet at the bottom of the ultracentrifuge tubes or as a floating layer at the top of the tubes a wide range of oils is suitable for the preparation of nanocapsules, including vegetable or mineral oils and pure compounds such as ethyl oleate and benzyl benzoate the criteria for selection are the absence of toxicity, lack of affinity for the coating polymer, the absence of risk of degradation of the polymer, and a high capacity to dissolve the drug that is entrapped generally, miglyol� is used to form the core of the nanocapsules, lipiodol� and benzyl benzoate have cheap viagra switch maestro also been successfully used to form nanocapsules soluble surfactants were chosen among poloxamers, triton x and tween in some cases, nanospheres formation together with nanocapsules were observed aprotic, fully watersoluble solvents such as acetone and acetonitrile lead to highquality nanocapsule preparations, whereas protic watermiscible solvents including ethanol, nbutanol, and isopropanol promoted the formation of nanospheres during nanocapsule preparation it has been hypothesized that alcohols potentially initiate the polymerization reaction of alkylcyanoacrylates to form polymer nuclei or preformed polymers that may precipitate as nanospheres, when the organic phase is added to the acqueous phase lowering the ph in the organic phase was shown to inhibit polymerization in this medium oilcontaining nanocapsules have been used to encapsulate cheap viagra switch maestro several types of biologically active compounds including both lipophilic molecules such as carbamazepine, indomethacin, lomustine, ethosuccimide, phenytoin, and hydrophilic drugs such as peptides the lipophilic drugs were solubilized in the organic phase and were encapsulated during the preparation of the nanocapsules, usually using ethanol as the watermiscible organic solvent the encapsulation efficiency of lipophilic drugs was found to be related to their solubility in the encapsulated oil quite surprisingly, hydrophilic compounds such as peptides have also been successfully encapsulated in oilcontaining nanocapsules indeed, these highly watersoluble compounds do not tend to dissolve in oil it has been suggested that the extremely rapid polymerization of the alkylcyanoacrylate occurring at the surface of the oil droplet limits the cheap viagra switch maestro diffusion of the peptide towards the acqueous phase, therefore leading to its entrapment in nanocapsules another explanation is that surfactants may form inverse micelles in the oily phase, allowing some dissolution of hydrophilic compounds in this phase interestingly, in contrast to what has been observed with polyalkylcyanoacrylate nanospheres, peptides do not react chemically with the alkylcyanoacrylate monomer during the preparation of nanocapsules when ethanol is used the presence of a large excess of alcohol seems to prevent the hydroxyl and amino groups of the peptides from reacting with the monomer, thus retaining the biological activity of the entrapped peptides, for example, encapsulated insulin was still recognized by the insulin receptor of hepatocytes after nanoencapsulation nanocapsules cheap viagra switch maestro containing an acqueous core nanocapsules with an acqueous core are a recent technology developed for the efficient encapsulation of watersoluble compounds, which are generally difficult to include within nanospheres they were obtained by interfacial polymerization, where the alkylcyanoacrylates monomers were added to a w� emulsion anionic polymerization of the cyanoacrylate in the oily phase was initiated at the interface by nucleophiles such as hydroxyl ions in the acqueous phase, leading to the formation of nanocapsules with an acqueous core in a typical procedure fig , an acqueous phase at ph , consisted of ethanol and water, was prepared this solution was emulsified in an organic phase containing miglyol� and montane� the slow addition hrs of the isobutylcyanoacrylate monomer cheap viagra switch maestro in the organic phase under mechanical stirring allowed the polymerization to occur this typical procedure leads to water droplets that are surrounded by a polymer core the oh cn coor ,oily phase fig schematic representation of the interfacial polymerization of cyanoacrylic monomers leading to the formation of nanocapsules with an acqueous core = monomer resuspension of the nanocapsules with a mean diameter approximately nm in a water phase has been achieved by the ultracentrifugation of the oily suspension, with an excess of demineralized water containing a surfactant after removal of the upper oily phase, the nanocapsules pellet was resuspended in water these nanocapsules are very useful for the encapsulation of hydrophilic compounds such as oligonucleotides cheap viagra switch maestro and peptides in this case, these macromolecules are dissolved in the acqueous phase before the interfacial polymerization process takes place for example, encapsulation efficiencies of with an oligothymidy late phosphodiester and of with a full phosphorothioate oligonucleotide directed against ews flichimeric rna were obtained these entrapment differences were attributed to possible interactions of the oligonucleotides with the oily phase, montane� , or to the possible location of the oligonucleotide at the wateroil interface which could become saturated the localization of the oligonucleotide within the acqueous core or adsorbed on the surface has been investigated through fluorescence quenching experiments using fluoresceinlabeled oligonucleotide and potassium iodine as an external quencher it has been shown that fluorescent oligonucleotides were located cheap viagra switch maestro in the acqueous core of the nanocapsules, surrounded by a polymeric wall, inaccessible to the quencher on the contrary, when the fluorescentoligonucleotides were free in solution, the fluorophores were highly accessible and strong quenching occurred similar quenching could be obtained with nanoencapsulated oligonucleotides only after the hydrolysis of the polymer wall, thus releasing the oligonucleotides zeta potential experiments have confirmed the localization of oligonucleotide in the acqueous core of the capsule moreover, nanoencapsulated oligonucleotides were protected against degradation by serum nucleases, phosphorothioate oligonucleotides directed against ews fli chimeric rna encapsulated within polyalkylcyanoacrylate nanocapsules were tested in vivo for their efficacy against the experimental ewing sarcoma in mice after intratumoral administration intratumoral injection of antisenseloaded nanocapsules cheap viagra switch maestro led to a significant inhibition of tumor growth, whereas no antisense effect could be detected with the free oligonucleotide these results were explained on the basis of a good protection of the oligonucleotide in the nanocapsules, which may act as a controled release system of oligonucleotide within the tumor salmon calcitonin was also successfully entrapped within poly butyl cyanoacrylate nanocapsules of nm in diameter when the diameter was reduced to nm, the encapsulation efficiencies decreased from to after storage at room temperature or at �c, the nanocapsules retained their size for at least months the encapsulated calcitonin remained stable at �c for one year polyalkylcyanoacrylate nanocapsules were also prepared by interfacial polymerization, using a microemulsion instead of an emulsion as the template microemulsions are spontaneously forming, thermodynamically stable dispersed systems having a uniform droplet size of less than nm as such, they represent an interesting system that may be exploited for the preparation of nanocapsules too practically, a pseudoternary phase diagram of a mixture of medium chain glycerides capryliccapric triglycerides and mono, diglycerides, a mixture of surfactants polysorbate and sorbitan monooleate and water was constructed microemulsion domains were characterized by conductivity and viscosity to select systems suitable for the interfacial polymerization of ethylcyanoacrylate nanocapsules of nm were obtained in those conditions and they were found to be able to encapsulate significant amounts of insulin size of the capsules may be controled, cheap viagra switch maestro depending on different formulation variables factors influencing the encapsulation of hydrophilic compounds have been identified too nanocapsules obtained from preformed polymers the preparation of nanocapsules from preformed polymers avoids some drawbacks of the interfacial polymerization process, such as the lack of control of the polymer molar masses and polydispersity, the presence of residual monomer in the preparation, and the possibility of drug inactivation an interfacial deposition process to prepare nanocapsules, also known as nanoprecipitation, has been developed, in this simple and reproducible method, a watermiscible organic phase such as an alcohol or a ketone containing oil with or without lipophilic surfactant is mixed with an acqueous phase containing a hydrophilic surfactant the preformed polymer, insoluble in cheap viagra switch maestro both the oily and the acqueous phase, is solubilized in the organic phase after the addition of the organic phase to the acqueous phase, the polymer diffuses with the organic solvent towards the acqueous phase and is stranded at the interface between oil and water the driving force for nanocapsule formation is the rapid diffusion of the organic solvent in the acqueous phase, inducing interfacial nanoprecipitation of the polymer surrounding the droplets of the oily phase synthetic polymers such as polyd,l lactide, polyecaprolactone and polyalkylcyanoacrylate are most frequently employed for nanocapsule formation arabic gum, gelatin, ethylcellulose or hydroxypropylmethylcellulose phthalate were also successfully used the size of nanocapsules is usually found between and nm, and cheap viagra switch maestro it depends on several factors, namely, the chemical nature and the concentration of the polymer and the encapsulated drug, the amount of surfactants, the ratio of organic solvent to water, the concentration of oil in the organic solution, and the speed of diffusion of the organic phase in the acqueous phase in general, the lower the interfacial tension and the viscosity of the oil, the smaller the nanocapsules are formed both lipophilic and hydrophilic surfactants are used in the preparation of nanocapsules by this technique however, not all the surfactants that are technically suitable are acceptable for parenteral administration as such, the choice has to be made with the administration route in mind generally, the lipophilic cheap viagra switch maestro surfactant is a natural lecithin of relatively low phosphatidylcholine content, whereas the hydrophilic one is ionic ie lauryl sulphate, quaternary ammonium, or more commonly nonionic ie polyoxyethylenepolypropropylene glycol polyethylene glycolcoated nanocapsules were also prepared by nanopre cipitation, using preformed diblock polylactidepolyethylene glycol copolymers or blends of these copolymers with the homopolymer polylactide however, the most physically stable nanocapsules were those prepared with polylactidepolyethylene glycol copolymer alone ru , a promising pure antiestrogen, was entrapped into polyethylene glycolcoated nanospheres and into nanocapsules with a similar coating a series of preformed diblock polyester polyethylene glycol copolymers were used for the design of these nanoparticles, both the molar masses of the polyethylene glycol blocks and the nature of the cheap viagra switch maestro hydrophobic polyester blocks being varied nanospheres which had a smaller size nm, compared with nanocapsules nm, were however able to incorporate larger amounts of the antioestrogen than the nanocapsules counterpart in an alternative method named solvent displacement method, an ow emulsion was formed the organic phase contained the polymer, the oil and the drug, and the acqueous solution contained a stabilizing agent in this procedure, the organic solvent was displaced into the external phase by the addition of an excess of water this technique has several advantages such as the small quantities of solvents used, the good control of the size of the nanocapsules nm, and the control of the thickness of the polymeric wall by cheap viagra switch maestro monitoring the polymer concentrations however, large amounts of water have to be removed at the end of the process two formulation processes which bring lipids into play should also be mentioned the first methodology is based on the inversion phase of an emulsion to prepare original lipidic nanocapsules these capsules, interestingly obtained as a suspension in saline water, were constituted by medium chain triglycerides and hydrophiliclipophilic surfactants according to the authors, the formulation method has been developed to avoid the use of organic solvent or the high quantity of surfactants and cosurfactants, due to the potential toxicity of their residues after human administration their original structure was found to be a hybrid between polymeric nanocapsules and cheap viagra switch maestro liposomes as their oily core is being surrounded by a tensioactive rigid membrane in another process, cisplatin lipidbased nanocapsules have been prepared by the repeated freezing and thawing of an equimolar dispersion of phosphatidylser ine ps and phosphatidylcholine pc in a concentrated acqueous solution of cisplatin here, the molecular architecture of these novel nanostructures was elucidated by solidstate nmr techniquesn nmr and h nmr spectra of nanocapsules containing sn and hlabeled cisplatin respectively, demonstrated that the core of the nanocapsules consists of solid cisplatin devoid of free water magic angle spinning n nmr showed that approximately of the cisplatin in the core is present as the dichloro species the remaining was accounted for by a cheap viagra switch maestro newly discovered dinuclear pt compound that was identified as the positively charged chloridebridged dimer of cisplatin nmr techniques, sensitive to lipid organization p nmr and h nmr, revealed that the cisplatin core is coated by phospholipids in a bilayer configuration and that the interaction between solid core and bilayer coat exerts a strong ordering effect on the phospholipid molecules compared with phospholipids in liposomal membranes, the motion of the phospholipid headgroups is restricted and the ordering of the acyl chains is increased, particularly in ps analysis of the mechanism of the nanocapsule formation suggests that the method may be generalized to include other drugs showing low water solubility and lipophilicity characterization size evaluation of nanocapsules is cheap viagra switch maestro most frequently done by photon correlation spectroscopy, transmission electron microscopy, and scanning electron microscopy, without or after freezefracture at present, transmission electron microscopy performed after freezefracture has given the most useful information about nanocapsule structure, highlighting the polymer envelope and the inner cavity, and allowing the wall thickness to be estimated, thus, polymer coatings were estimated to be around nm, depending on the monomer concentration freeze fracture fig has also allowed the visualization of different possible organizations of lipophilic surfactant, which can form vesicles, micelles, bilayers, or monolayers, depending on its concentration the spherical shape of the nanocapsules was confirmed by atomic force microscopy most images of nanocapsules have been obtained by transmission electron microscopy cheap viagra switch maestro performed on negatively stained preparations, allowing to gain information about nanocapsule morphology and integrity, fig �� nanocapsules embedded in a suitable resin were cut into thin slices they were observed using electron microscopy, the contrast being created by encapsulation of a colloidal goldlabeled molecule during nanocapsule preparation in this manner, both polymer envelope and the internal cavity were distinguished easily fig b a nm nm nm fig a morphological appearance of polydactic acidcoglycolic nanocapsules using the transmission electron microscopy � labeling insulin with gold allows to distinguish the localization of this molecule into the internal core of polyisobutyl cyanoacrylate nanocapsules transmission electron microscopy � zeta potential measurements are also very useful for the chraracterization of the cheap viagra switch maestro nanocapsules surfactants and polymer are the major components that can affect this parameter many polymers such as poly d,llactide, polyecaprolactone and lecithins impart a negative charge to the surface, whereas nonionic surfactants such as poloxamer tend to reduce the absolute value of zeta potential calvo et alp described nanocapsules coated with positively charged polysaccharide chitosan their surface charge depended mainly on the viscosity of the chitosan solution used for coating positive values up to mv were also observed with diethylaminoethyl dextran coated nanocapsules generally, zeta potential values above mv positive or negative values lead to more stable nanocapsule suspensions, because repulsion between the particles prevented their aggregation in contrast to observations with nanospheres, the cheap viagra switch maestro negative zeta potential of the nanocapsules was not completely masked by the presence of neutral polyethylene glycol chains at the surface this was due to the presence of lecithin in the polyethylene glycol brush, which remained necessary for nanocapsule stability it was further highlighted that the presence of such a brush could reduce complement activation, an important step in the recognition of particles by macrophages centrifugation in a density gradient was used to confirm the existence of nanocapsules by comparing with the colloidal carriers prepared without polymer or oil for example, isopycnic centrifugation in a density gradient of per coll was used in the case of nanocapsules with a miglyol core and a coating of poly cheap viagra switch maestro alky lcyanoacry late or polyd,l lactide the density of the nanocapsules was found to be intermediate between that of nanospheres and that of emulsions these studies also demonstrated that the density of nanocapsules and the band thickness increased when the quantity of polymer increased no contamination of nanocapsules with nanospheres was observed however, mosqueira et ali performed similar experiments and observed that nanocapsule preparations obtained by nanoprecipitation contained small amounts of nanospheres, as it has previously been described by gallardo et al for nanocapsules prepared by interfacial polymerization when lecithin was present in excess as lipophilic surfactant, liposomes were also detected in the nanocapsule preparations liposomes could not be distinguished from nanocapsules on the cheap viagra switch maestro basis of density differences, but have been detected by electron microscopy and by the encapsulation of an acqueous tracer drug release release of encapsulated drugs from nanocapsules made of preformed polymers, appears only to be controled by the partition coefficient of the drug between the oily core and the acqueous external medium, and the relative volumes of these two phases except for macromolecules, the rate of diffusion of the drug through the thin polymeric coating does not seem to be a limiting factor, nor does the nature of the polymeric wall this clearly suggests that the polymer membrane may be porous rather than a continuous film barrier to diffusional release the nature of the external acqueous cheap viagra switch maestro phase is of prime importance in the release for example, indomethacin release was faster and more complete in the presence of albumin, which acts as an acceptor in the acqueous phase similarly, release of halofantrine, a highly lipophilic drug, was only observed in the presence of serum, because the drug has a high affinity for lipoproteins the presence of a hydrophilic polyethylene glycol brush at the nanocapsule surface was also shown to play a role in drug release release of halofantrine and primaquine from such surfacemodified nanocapsules was reduced, compared with conventional nanocapsules in conclusion, it may be considered a challenge to develop nanocapsule systems with release profiles, which may be controled not only by cheap viagra switch maestro the partitioning coefficient, but also by the nature or morphology ie thickness or porosity of the surrounding membrane applications nanocapsules have been proposed as drug delivery systems for several drugs by different routes of administration such as oral, ocular or parenteral drugloaded nanocapsules were used to improve the stability of the drug either in biological fluids, or simply in the formulation another goal was to reduce the toxicity of some drugs known for their undesirable side effects oral route challenging aspects related to oral administration deal with the entrapment of unstable molecules, such as peptides or that of antiinflammatory compounds that cause local side effects on the mucosae pioneering studies in the mid s dealt with cheap viagra switch maestro indomethacin and insulin entrapment indomethacin, an anti inflammatory drug, has been successfully encapsulated in the polyalkylcyanoacrylate nanocapsules with the aim of reducing its side effects on the gastric and intestinal mucosa the drug retained its biological activity after nanoencapsulation moreover, nanoencapsulated formulations allowed a dramatic reduction of the ulcerative side effects usually induced by indomethacin on the mucosae this protection was attributed to the combined effect of the sustained release of indomethacin from the nanocapsules, with a significant reduction of the direct contact between drug and the mucosae in the case of nanocapsules obtained by nanoprecipitation using polyesters, the release kinetics in media mimicking ph of the gut were more sensitive to changes in drug partitioning related to the change of ph, than to the type of polymer used, drug release from nanocapsules was accelerated in the presence of digestive enzymes such as proteases and esterases this was correlated with a decrease in polymer molecular weight diclofenac and indomethacin, two major nonsteroidal anti inflammatory agents, have been encapsulated in polylactic acid nanocapsules obtained by nanoprecipitation, with the aim of reducing their side effects on the gastric mucosa the side effects of both drugs were completely modified and reduced by the encapsulation in nanocapsules as in the case of nanocapsules produced by interfacial polymerization, a marked protective effect on the gastrointestinal mucosa, as compared with the ulcerative effect observed with the drug cheap viagra switch maestro solutions, was observed insulinloaded nanocapsules yielded promising pharmacological results, when given orally to diabetic rats and dogs, single administration produced a reduction in glycemia after an unusually long lag of several days, and this hypoglycemia was sustained for up to days, it was suggested that nanocapsules could release insulin slowly from a depot within the body the nanocapsules seemed to be involved in carrying the insulin near the intestinal epithelium where they were absorbed and translocated as intact nanocapsules to the blood vessels, however, lowe and temple reported that insulin adsorption from orally administered nanocapsules reached a maximum of absorption, min after administration and any trace of insulin in blood was detected after a few cheap viagra switch maestro hours sai et alb have proposed the use of insulinloaded nanocapsules as a new prophylactic tool to prevent diabetes they showed in a model of nonobese diabetic mice that prophylactic injection of such nanocapsules reduced the incidence of diabetes anti infectious agents such as atovaquone and rifabutin, two compounds active against the opportunistic parasite toxoplasma gondii, were successfully entrapped in polylactide nanocapsules formed by nanoprecipitation these drugs have a poor bioavailability because of their insolubility in water nanoencapsulation is allowed to decrease in the brain parasitic burden in a higher extent than the same amount of free drug chitosancoated nanocapsules were particularly interesting for oral administration, probably because their positive charge allow them to stick efficiently cheap viagra switch maestro along the gastrointestinal mucosa, with a further possible diffusion through the epithelium , thus providing a continuous drug delivery into the blood stream, when the peptide salmon calcitonin was entrapped into these nanocapsules, longlasting hypocalcemia effects were observed, following oral administration to rats in contrast, calcitonin control emulsions led to negligible responses parenteral route as far as the parenteral route is concerned, nanocapsules could be useful for the formulation of poorly soluble drugs, and for controling the drug biodistribution according to the properties of the carrier in this view, indomethacin and diclofenac were entrapped in nanocapsules, but diclofenac in solution or in nanocapsules showed similar plasma concentration profiles after intravenous administration, encapsulated indomethacin showed even lower cheap viagra switch maestro plasma concentrations than the free drug because of enhanced hepatic uptake of loaded nanocapsules one possible explanation for the absence of the modification of the pharmacokinetics and biodistribution profiles of the encapsulated drugs probably results from the rapid rate of release of these drugs into the circulation, due to the high blood dilution andor the presence of plasma proteins subcutaneous injection did not lead to a slow release of the drug either nevertheless, after intramuscular administration, the nanocapsules containing diclofenac showed a significantly reduced inflammation at the site of injection, compared with the free drug in solution similarly, darodipine nanocapsules provided a prolonged antihypertensive effect compared with free drug which lasted for at least hrs nanocapsules cheap viagra switch maestro prepared by interfacial polymerization of the isobutylcyanoacry late monomers were retained longer at the injection site after intramuscular administration than the other types of carriers such as emulsions or liposomes moreover, they were taken up to a significant extent by the regional lymph nodes, likely owing to the phagocytosis by macrophages these observations open up the possibility of delivering cytostatic drugs and immunomodulators to the lymph node metastases when administered intravenously, nanocapsules made by interfacial polymerization or by nanoprecipitation were taken up rapidly by organs of the mononuclear phagocyte system, mainly the liver to take advantage of this particular tissue distribution, nanocapsules containing muramyltripeptide cholesterol mtp chol were designed, this immunostimulating agent, able to activate cheap viagra switch maestro the macrophages and to stimulate their innate defense functions against tumor cells, is a useful agent to treat metastatic cancer in vitro studies with rat alveolar macrophages have shown that nanocapsules prepared from polyd,llactic acid containing mtp chol were more efficient activators than the free drug this was attributed to the intracellular delivery of the nanoencapsulated immunomodulator after cell phagocytosis an intermediate transfer of the drug to serum proteins was another suggested mechanism in vivo, this type of nanocapsules is allowed to obtain significant antimetastatic effects in a model of liver metastases for other types of applications, to avoid the rapid clearance by the mononuclear phagocyte system, nanocapsules coated with polyethylene glycol with a molar cheap viagra switch maestro mass of , gmole were developed an antimalarial drug, halofantrine, was entrapped with the aim of obtaining a welltolerated injectable form for the treatment of this severe intravascular disease in mice, at an advanced stage of infection with plasmodium berghei, the area under the curve for plasma halofantrine was increased sixfold, compared with the free drug when the molecule was presented as nanocapsules moreover, the toxicity of halofantrine was reduced by incorporation into the nanocapsules up to mgkg could be administered intravenously without toxicity, yet all mice injected with this dose of free halofantrine died instantaneously however, in vivo, only small differences were observed in terms of the therapeutic activity between polyethylene glycol coated nanocapsules and cheap viagra switch maestro the uncoated ones this was explained by the possible saturation of the phagocytic capacity of the liver in severely infected mice, as a result of the uptake of parasitized erythrocytes moreover, it was emphasized that the amount of serum lipoproteins, which acted as acceptors for halofantrine released from nanocapsules, is reduced during the disease polyethylene glycol coated nanocapsules were also used to deliver lipophilic drugs to the solid tumors in this case, the vascular endothelium is known to be more permeable, thus allowing the extravasation of smallsized colloidal particles this specific distribution of colloids into tumoral sites is known as the enhanced permeability and retention effect epr effect the efficacy of this strategy has been demonstrated cheap viagra switch maestro using a photosensitizer, metatetra hydroxyphenyl chlorine, encapsulated in nanocapsules designed from diblock polyd,l lactidepolyethylene glycol copolymers ocular delivery the major problems encountered when delivering drugs to the eyes are the poor permeability of the corneal epithelium and the rapid clearance because of tear turnover and lacrimal drainage nanocapsule formulations were developed with the aim of improving drug efficacy by retaining it at the level of the ocular tissue, thus reducing the number of administrations betaxololloaded polyisobutylcyanoacrylate nanocapsules made by interfacial polymerization were prepared for the treatment of glaucoma only a marginal decrease in the intraocular pressure was observed with this type of formulation, compared with the activity obtained with the commercial form single solution cheap viagra switch maestro or by other carriers more promising results have been obtained with pilocarpine in this case, sustained drug release was obtained when incorporating the pilocarpine loaded nanocapsules into a pluronic gel thus, a significant increase in the bioavailability of the drug was achieved ganciclovir is an antiviral drug used for the treatment of cytomegalovirus infections in the clinical practice, two to three intravitreal injections per week are needed to overcome the rapid clearance of the drug from the eyes ganciclovir encapsulation in polyethylcyanoacrylate nanocapsules made by interfacial polymerization provided a sustained release of the drug over four days moreover, after intravitreal injection of the nanocapsules, the drug could still be detected in the eyes at a therapeutic cheap viagra switch maestro level after ten days significant amounts of ganciclovir were found in the retina and in the vitreous humor which is considered as beneficial in the treatment of cytomegalovirus retinitis on the contrary, after administration of single solutions of the drug free, the maximum concentration of ganciclovir was reached in less than one day and no drug could be detected later however, despite these beneficial results, some toxicity opacification of the lens and vitreous humor turbidity was found as a result of the nanocapsules antiglaucomatous agents such as carteolol and betaxolol were also encapsulated in nanocapsules prepared from preformed polymers, but they only showed a reduction of the noncorneal absorption systemic circulation, leading to lesser side cheap viagra switch maestro effects as compared with the free drug encapsulation in nanocapsules produced an improved pharmacological effect characterized by a more important reduction of the intraocular pressure, compared with the free drug treatment, as well as with the same treatment but delivered by nanospheres reduced cardiovascular systemic side effects were also observed with the nanocapsules, in the case of betaxolol, the nature of the polymer making up the nanocapsule wall was found to play a major role in the pharmacological responses, thus, polyecaprolactone walls were more efficient than polyisobutylcyanocrylate or polylactidecoglycolide ones indeed, as shown by the confocal microscopy, polyecaprolactone nanocapsules could specifically penetrate the corneal epithelium by an endocytic process, without causing any damage to the cells cheap viagra switch maestro in contrast, polyisobutylcyanoacrylate nanoparticles produced a cellular lysis as no differences in penetration were observed between nanospheres and nanocapsules, the presence of an oily core did not seem to influence activity of the formulation coating the negatively charged surface of polyecaprolactone nanocapsules with chitosan, a cationic polymer, provided the best corneal drug penetration, together with preventing the degradation caused by the adsorption of lysozyme, a positively charged enzyme found in tear fluid this was explained by the higher penetration of the nanocapsules into the corneal epithelial cells and by the mucoadhesion of these positively charged particles onto the negatively charged membranes additionally, a specific effect of chitosan on the tight junctions has been mentioned encouraging results cheap viagra switch maestro were also obtained with nanocapsules containing the immunosuppressive peptide cyclosporin a this drug was efficiently entrapped in polyecaprolactone nanocapsules, leading to a fivefold increase of the cyclosporin a corneal concentrations, compared with an oily solution of the drug again, chitosanovercoated nanocapsules were able to provide a selective and prolonged delivery of cyclosporine a to the ocular mucosae, without compromising the inner ocular tissues and avoiding systemic absorption the mechanism that explains the increased ocular penetration was understood as the combination of an improved interaction with the corneal epithelium, followed by the penetration of the particles into the corneal epithelium in the case of indomethacin associated with chitosanecoated nanocapsules, the use of confocal microscopy established the cheap viagra switch maestro fact that the nanocapsules penetrated through the corneal epithelium following a transcellular pathway conclusion as discussed in this chapter, there are now various technologies for the preparation of nanocapsules these methods which obey a wide variety of principles may either start from a monomer or from a preformed polymer they employ macromolecular materials of synthetic or natural origin and they allow the design of nanocapsules with either an acqueous or an oily core thus, they can efficiently entrap almost every molecule the most significant advantage of nanocapsules over nanospheres is that the drug to polymer ratio is generally much higher, which allows the use of lesser polymer to deliver the same amount of drug to the cheap viagra switch maestro cells and tissues this is, from a toxicological point of view, a substantial advantage of this type of technology on the contrary, drug release from nanocapsules is mainly dependent on the partitioning coefficient of the biologically active compound between the nanocapsule core and the biological receptor medium if the nanocapsule thin polymer membrane may be a barrier for the diffusion of macromolecules, it is not the case for small organic molecules thus, to control the drug release kinetic from nanocapsules, it is likely to remain the primary challenge to be resolved with this kind of technology in the next few years references fresta m, cavallaro g, giammona g, wehrli e and puglisi g preparation and cheap viagra switch maestro characterization of polyethylcyanoacrylate nanocapsules containing antiepileptic drugs biomaterials fattal e, peracchia mt and couvreur p polyalkylcyanoacrylate, in domb aj, kost j, wiseman dm eds handbook of biodegradable polymers harwood academic publishers amsterdam al khouri n, fessi h, roblottreupel l, devissaguet jp and puisieux f an original procedure for preparing nanocapsules of polyalkylcyanoacrylates for interfacial polymerization pharm acta helv al khouri fallouh n, roblottreupel l, fessi h, devissaguet jp and puisieux f development of a new process for the manufacture of polyisobutylcyanoacrylate nanocapsules int f pharm gallardo mm, couarraze g, denizot b, treupel l, couvreur p and puisieux f preparation and purification of isohexylcyanoacrylate nanocapsules int} pharm wohlgemuth m, machtle w and mayer � improved preparation and cheap viagra switch maestro physical studies of polybutylcyanoacrylate nanocapsules j microencapsulation chouinard f, kan fw, leroux jc, foucher � and lenaerts v preparation and purification of polyisohexylcyanoacrylate nanocapsules int j pharm chouinard f, buczkowski s and lenaerts v polyalkylcyanoacrylate nanocapsules physicochemical characterization and mechanism of formation pharm res puglisi g, fresta m, giammona g and venture ca influence of the preparation conditions in polyethylcyanoacrylate nanocapsules formation int j pharm elsamaligy ms, rojanasakul y, charlton jf, weinstein gw and lim jk ocular disposition of nanoencapsulated acyclovir and ganciclovir via intravitreal injection in rabbits eye drug del ammoury n, fessi h, devissaguet jp, puisieux f and benita s physicochemical characterization of polymeric nanocapsules and in vitro release evaluation of indomethacin as cheap viagra switch maestro a drug model stp pharm giirsoy a, eroglu l, ulutin s, tasyiirek m, fessi h, puisieux f and devissaguet jp evaluation of indomethacin nanocapsules for their physical stability and inhibitory activity on inflammation and platelet aggregation int j pharm marchalheussler l, fessi h, devissaguet jp, hoffman m and maincent p generic medicine for cozaar colloidal drug delivery systems for the eye a comparison of the efficacy of three different polymers polyisobutylcyanoacrylate, polylacticcoglycolic acid, polyepsilon caprolactone stp pharm sci desai sd and blanchard j pluronic� fbased ocular delivery systems containing biodegradable polyisobutylcyanoacrylate nanocapsules of pilocarpine drug del j aboubakar m, puisieux f, couvreur p, deyme m and vauthier � study of the mechanism of insulin encapsulation in polyisobutylcyanoacrylate nanocapsules obtained by cheap viagra switch maestro interfacial polymerization biomed mater res damge c, michel c, aprahamiam m and couvreur p new approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier diabetes lowe pj and temple cs calcitonin and insulin in isobutylcyanoacrylate nanocapsules protection against proteases and effect in intestinal absorption in rats } pharm pharmacol damge c, vonderscher j, marbach p and pinget m polyalkylcyanoacrylate nanocapsules as a delivery system in the rat for octreotide, a longacting somatostatin analogue } pharm pharmacol damge c, vranckx h, baldschmidt p and couvreur p polyalkylcyanoacrylate nanospheres for oral administration of insulin } pharm sci michel c, aprahamiam m, defontaine l, couvreur p and damge � the effect of site of administration cheap viagra switch maestro in the gastrointestinal tract on the absorption of insulin from nanocapsules in diabetic rats j pharm pharmacol damge c, hillairebuys d, puech r, hoelizel a, michel � and ribes g effects of orally administered insulin nanocapsules to normal and diabetic dogs diabetes nutr metab roques m, damge c, michel c, staedel c, cremel g and hubert p encapsulation of insulin for oral administration preserves interaction of the hormone with its receptor in vitro diabetes lambert g, fattal e, pintoalphandary h, gulik a and couvreur p polyisobutylcyanoacrylate nanocapsules containing an acqueous core as a novel colloidal carrier for the delivery of oligonucleotides pharm res lambert g, bertrand jr, fattal e, subra f, pintoalphandary h, malvy c, auclair cheap viagra switch maestro � and couvreur p ews fli antisense nanocapsules inhibits ewing sarcomarelated tumor in mice bbrc chavany c, le doan t, couvreur p, puisieux f and helene � polyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides pharm res nakada y, fattal e, foulquier m and couvreur p pharmacokinetics and biodistribution of oligonucleotide adsorbed onto polyisobutylcyanoacrylate nanoparticles after intravenous administration in mice pharm res vrankx h, demoustier m and deleers m a new nanocapsule formulation with hydrophilic core application to the oral administration of salmon calcitonin in rats eur j pharm biopharm watnasirichaikul s, da vies nm, rades t and tucker ig preparation of biodegradable insulin nanocapsules from biocompatible microemulsions pharm res watnasirichaikul s, rades t, tucker cheap viagra switch maestro ig and davies nm effects of formulation variables on characteristics of poly ethylcyanoacrylate nanocapsules prepared from wo microemulsions int j pharm pitaksuteepong t, davies nm, tucker ig and rades t factors influencing the entrapment of hydrophilic compounds in nanocapsules prepared by interfacial polymerisation of waterinoil microemulsions eur } pharm biopharm grangier jl, puygrenier m, gauthier jc and couvreur p nanoparticles as carriers for growth hormone releasing factor grf j control rel fessi h, devissaguet jp and puisieux f precede de preparation des systemes colloidaux dispersibles dune substance sous forme de nanocapsules french patent application no fessi h, puisieux f, devissaguet jp, ammoury n and benita s nanocapsule formation by interfacial deposition following solvent displacement int j cheap viagra switch maestro pharm rr mosqueira vcf, legrand p, pintoalphandary h, puisieux f and barratt g polyd,llactide nanocapsules prepared by a solvent displacement process influence of the composition on physicochemical and structural properties j pharm sci bourdon o, mosqueira v, legrand p and blais j a comparative study of the cellular uptake, localization and phototoxicity of metatetrahydroxyphenyl chlorine encapsulated in surfacemodified submicronic oilwater carriers in ht tumor cells } photochem photobiol � mosqueira vcf, legrand p, gref r and barratt g in vitro release kinetic studies of pegmodified nanocapsules and nanospheres loaded with a lipophilic drug halofantrine base proceedings of the th international symposium on controlled release of bioactive materials, june, boston, ma ameller t, marsaud v, cheap viagra switch maestro legrand p, gref r and barratt g et renoir jm polyester � polyethylene glycol nanospheres and nanocapsules loaded with the pure antioestrogen ru physicochemical and opsonisation properties pharm res ameller t, marsaud v, legrand p, gref r and barratt g et renoir jm polyester � polyethylene glycol nanospheres and nanocapsules loaded with the pure antioestrogen ru physicochemical and opsonisation properties pharm res quintanarguerrero d, allemann e, doelker e and fessi h preparation and characterization of nanocapsules from preformed polymers by a new process based on emulsificationdiffusion technique pharm res quintanarguerrero d, fessi h, doelker e and allemann e precede de preparation de nanocapsules de type vesiculate utilisable notamment comme vecteurs colloidaux de principes actifs pharmaceutiques ou cheap viagra switch maestro autres, french patent heurtault b, saulnier p, pech b, proust je and benoit jp a novel phase inversion based process for the preparation of lipid nanocarriers pharm res heurtault b, saulnier p, pech b, proust je and benoit jp properties of polyethyleneglycol hydroxystearate at the triglyceridewater interface int j pharm heurtault b, saulnier p, pech b, venierjulienne mc, proust je, phantanluu r and benoit jp the influence of lipid nanocapsule composition on their size distribution eur pharm sci chupin v, de kroon al and de kruijff � molecular architecture of nanocapsules, bilayerenclosed solid particles of cisplatin j am chem soc burger kn, staffhorst rw, de vijlder hc, velinova mj, bomans ph, frederik pm and de cheap viagra switch maestro kruijff � nanocapsules lipidcoated aggregates of cisplatin with high cytotoxicity nat med magalhaes ns, fessi h, puisieux f, benita s and seiller m an in vitro release kinetic examination and comparative evaluation between submicron emulsion and polylactic acid nanocapsules of clofibride j microencapsul rollot jm, couvreur p, roblottreupel l and puisieux f physicochemical and morphological characterization of polyisobutyl cyanoacrylate nanocapsules } pharm sci vauthier c, dubernet c, fattal e, pintoalphandary h and couvreur p polyalkylcyanoacrylates as biodegradable materials for biomedical applications adv drug del rev calvo p, remunanlopez c, vilajato jl and alonso mj development of positively charged colloidal drug carriers chitosancoated polyester nanocapsules and submicron emulsions coll polym sci mosqueira vcf, legrand p, gulik a, cheap viagra switch maestro bourdon o, gref r, labarre d and barratt g relationship between complement activation, cellular uptake and surface physicochemical aspects of novel pegmodified nanocapsules biomaterials mosqueira vcf, legrand p, gref r, heurtault b, appel m and barratt g interactions between a macrophage cell line ja and surfacemodified polyd,llactide nanocapsules bearing polyethylene glycol j drug targ ammoury n, fessi h, devissaguet jp, puisieux f and benita s in vitro release kinetic pattern of indomethacin from polyd,llactide nanocapsules j pharm sci ��� heurtault b, legrand p, mosqueira v, devissaguet jp, barratt g and bories � in vitro antileishmanial properties of surface modified and primaquine loaded nanocapsules in leishmania donovani intramacrophagic amastigotes ann trop med parasitol ammoury cheap viagra switch maestro n, fessi h, devissaguet jp, dubrasquet m and benita s jejunal absorption, pharmacological activity, and pharmacokinetic evaluation of indomethacinloaded polyd,llactide and polyisobutylcyanoacrylate nanocapsules in rats pharm res marchais h, benali s, irache jm, tharassebloch c, lafont � and orecchioni am entrapment efficiency and initial release of phenylbutazone from nanocapsules prepared from different polyesters drug dev ind pharm kedzierewicz f, thouvenot p, monot i, hoffman m and maincent p influence of different physicochemical conditions on the release of indium oxine from nanocapsules j biomed mater res guterres ss, fessi h, barratt g, puisieux f and devissaguet jp polyd,llactide nanocapsules containing nonsteroidal antiinflammatory drugs gastrointestinal tolerance following intravenous and oral administration pharm res andrieu v, fessi cheap viagra switch maestro h, dubrasquet m, devissaguet jp, puisieux f and benita s pharmacokinetic evaluation of indomethacin nanocapsules drug des del damge c, michel c, aprahamiam m, couvreur p and devissaguet jp nanocapsules as carriers for oral peptide delivery ] control rel aboubakar m, couvreur p, pintoalphandary h, gouritin b, lacour b, farinotti r, et al insulinloaded nanocapsules for oral administration in vitro and in vivo investigation drug dev res aprahamiam m, michel c, humbert w, devissaguet jp and damge � transmu cosal passage of polyalkylcyanoacrylate nanocapsules as a new drug carrier in the small intestine biol cell sai p, damge c, rivereau as, hoeltzel a and gouin e prophylactic oral administration of metabolically active insulin entrapped in cheap viagra switch maestro isobutylcyanoacrylate nanocapsules reduces the incidence of diabetes in nonobese diabetic mice ] autoimmunity dalengon f, amjaud y, lafforgue c, derouin f and fessi h atovaquone and rifabutineloaded nanocapsules formulation studies int j pharm calvo p, remunan c, vila jato jl and alonso mj development of positively charged colloidal drug carriers chitosancoated polyester nanocapsules and submicron emulsions coll polym sci vila a, sanchez a, evora c, soriano i, vila jato jl and alonso mj pegpla nanoparticles as carriers for nasal proteinvaccine delivery j aerosol med prego c, fernandezmegia e, novoacarballal r, quinoa e, torres d and alonso mj chitosan and chitosanpeg nanocapsules new carriers for improving the oral absorption of calcitonin guterres ss, fessi h, barratt g, cheap viagra switch maestro puisieux f and devissaguet jp polyd,llactide nanocapsules containing diclofenac protection from muscular damage in rats j biomater sci polym ed hubert b, atkinson j, guerret m, hoffman m, devissaguet jp and maincent p the preparation and acute antihypertensive effects of a nanocapsular form of darodipine, a dihydropyridine calcium entry blocker pharm res nishioka y and yoshino h lymphatic targeting with nanoparticulate system adv drug del rev marchalheussler l, thouvenot p, hoffman m and maincent p comparison of the biodistribution in mice of illindium oxine encapsulated into polylacticcoglycolic d,l and polyepsiloncaprolactone nanocapsules j pharm sci morin c, barratt g, fessi h, devissaguet jp and puisieux f improved intracellular delivery of a muramyl dipeptide analog cheap viagra switch maestro by means of nanocapsules int j immunophar macol seyler i, appel m, devissaguet jp, legrand p and barratt g relationship between nosynthase activity and tnfalpha secretion in mouse macrophage lines stimulated by a muramyl peptide entrapped in nanocapsules int j immunopharmacol seyler i, appel m, devissaguet jp, legrand p and barratt g macrophage activation by a lipophilic derivative of muramyldipeptide within nanocapsules investigation of the mechanism of drug delivery nanoparticle res barratt g, puisieux f, yu wp, foucher c, fessi h and devissaguet jp anti metastatic activity of mdplalanylcholesterol incorporated into various types of nanocapsules int j immunopharmacol mosqueira vcf, legrand p, bories c, devissaguet jp and barratt g comparative pharmacokinetics and in vivo efficacy of cheap viagra switch maestro an intravenous formulation of halofantrine in longcirculating nanocapsules in plasmodium bergheiinfected mice proceedings of the th international symposium on controlled release of bioactive materials, july paris, france langer k, zimmer a and kreuter j acrylic nanoparticles for ocular drug delivery stp pharm sci legrand p, barratt g, mosqueira v, fessi h and devissaguet jp polymeric nanocapsules as drug delivery systems, a review stp pharm sci marchalheussler l, sirbat d, hoffman m and maincent p polyepsilon caprolactone nanocapsules in carteolol ophthalmic delivery pharm res losa c, marchalheussler l, orallo f, vila jato jl and alonso mj design of new formulations for topical ocular administration polymeric nanocapsules containing metipranolol pharm res calvo p, thomas c, alonso mj, cheap viagra switch maestro vila jato jl and robinson jr study of the mechanism of interaction of polyecaprolactone nanocapsules with the cornea by confocal laser scanning microscopy int j pharm zimmer a, kreuter j and robinson jr studies on the transport pathway of pbca nanoparticles in ocular tissues} microencapsulation calvo p, vilajato jl and alonso mj effect of lysozyme on the stability of polyester nanocapsules and nanoparticles stabilization approaches biomaterials calvo p, vilajato jl and alonso mj evaluation of cationic polymercoated nanocapsules as ocular drug carriers int j pharm de campos a, sanchez a and alonso mj chitosan nanoparticles a new vehicle for the improvement of the ocular retention of drugs application to cyclosporin a int ] pharm de campos cheap viagra switch maestro a, sanchez a and alonso mj the effect of a peg vs a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa eur j pharm sci calvo p, vilajato jl and alonso mj evaluation of cationic polymercoated nanocapsules as ocular drug carriers int j pharm dendrimers as nanoparticulate drug carriers ssnke svenson and donald a tomalia introduction the development of molecular nanostructures with welldefined particle size and shape is of eminent interest in biomedical applications such as the delivery of active pharmaceuticals, imaging agents, or gene transfection for example, constructs utilized as carriers in drug delivery generally should be in the nanometer range and uniform in size to enhance their ability cheap viagra switch maestro to cross cell membranes and reduce the risk of undesired clearance from the body through the liver or spleen two traditional routes to produce particles that will meet some of these requirements have been widely investigated the first route takes advantage of the ability of amphiphilic molecules ie molecules consisting of a hydrophilic and hydrophobic moiety to selfassemble in water above a systemspecific critical micelle concentration cmc to form micelles size and shape of these micelles depend on the geometry of the constituent monomers, intermolecular interactions, and conditions of the bulk solution ie concentration, ionic strength, ph, and temperature spherical micelles are monodisperse in size however, they are highly dynamic in nature with monomer exchange rates cheap viagra switch maestro in millisecond to microsecond time ranges micelles have the ability to encapsulate and carry lipophilic actives within their hydrocarbon cores depending on the specific system, some micelles either spontaneously rearrange to form liposomes after a minor change of solution conditions, or when they are exposed to external energy input such as agitation, sonication, or extrusion through a filter membrane liposomes consist of bilayer lipid membranes blm enclosing an aqueous core, which can be utilized to carry hydrophilic actives furthermore, liposomes with multilamellar membranes provide cargo space for lipophilic actives as well however, most liposomes are considered energetically metastable, and will eventually rearrange to form planar bilayers the second route relies on engineering the welldefined particles through cheap viagra switch maestro processing protocols examples for this approach include i shearing or homogenization of oilinwater �w emulsions or w�w double emulsions to produce stable and monodisperse droplets, ii extrusion of polymer strands or viscous gels through nozzles of defined size to manufacture stable and monodisperse micro and nanospheres, iii layerbylayer lbl deposition of polyelectrolytes and other polymeric molecules around colloidal cores, resulting in the formation of monodisperse nanocapsules after the removal of the templating core, and iv controlled precipitation from a solution into an antisolvent, including supercritical fluids size, degree of monodispersity, and stability of these structures depend on the systems that are being used in these applications these systems and their utilization in drug delivery are being discussed in detail in other chapters of this book currently, a new third route to create very welldefined, monodisperse, stable molecular level nanostructures is being studied based on the dendritic state architecture dendritic architecture is undoubtedly one of the most pervasive topologies observed throughout biological systems at virtually all dimensional length scales this architecture is found at the meter scale in tree branching and roots, on the centimeter and millimeter scales in circulatory topologies in the human anatomy such as lungs, kidney, liver, and spleen, and on the micrometer scale in cerebral neurons on the nanometer level, key examples of dendritic structures include glycogen, amylopectin, and proteoglycans amylopectins and glycogen are critical molecular level constructs cheap viagra switch maestro involved in energy storage in plants and animals, while proteoglycans are an important constituent of connective tissue, determining its viscoelastic properties upon the analysis of these ubiquitous dendritic patterns, it is evident that these highly branched architectures offer unique interfacial and functional performance advantages the objective of this review is to study the use of dendrimers in drug delivery applications four main properties of dendrimers will be discussed i nanoscale container properties ie encapsulation and transport of a drug, ii nanoscaffolding properties ie surface adsorption or attachment of a drug andor targeting ligand, iii dendrimers as drugs, and iv biocompatibility of dendrimers in addition, routes of application currently investigated will be presented particular emphasis will cheap viagra switch maestro be placed on poly amidoamine ����� dendrimers, the first and most extensively studied family of dendrimers nanoscale containers � micelles, dendritic boxes, dendrophanes, and dendroclefts dendrimers may be visualized as consisting of three critical architectural domains i the multivalent surface, containing a larger number of potentially reactive passive sites nanoscaffolding, ii the interior shells ie branch cell layers defined by dendrons surrounding the core, and iii the core to which the dendrons are attached the two latter domains represent welldefined nanoenvironments, which are protected from the outside by the dendrimer surface nanoscale containers in the case of higher generation dendrimers these domains can be tailored for a specific purpose the interior is wellsuited for hostguest interaction cheap viagra switch maestro and the encapsulation of guest molecules dendritic micelles tomalia and coworkers demonstrated by electron microscopy observation that sodium carboxylated ����� dendrimers possess topologies reminiscent of regular classical micelles it was also noted from electron micrographs that a large population of individual dendrimers possessed a hollow core supporting these observations, turro and colleagues designed a hydrophobic carbon atom alky lene chain into the core of a homologous series of ����� dendrimers g , and to mimic the hydrophobic and hydrophilic coreshell topology of a regular micelle the hosting properties of this series towards a hydrophobic dye as a guest molecule were then compared with � ����� dendrimer series possessing nonhydrophobic cores eg nh and ethylenediamine dramatically enhanced cheap viagra switch maestro emission of the hydrophobic dye was noted in aqueous solution in the presence of hydrophobic versus hydrophilic cored dendrimers� less polar dendrimers ie dendrimers containing aryl groups or other hydrophobic moieties as building elements, behave as inverse micellesb a critical property difference relative to micelles is the increased density of surface groups with higher generations at some generational level, the surface groups will reach the socalled de gennes dense packing limit and seal the interior from the bulk solution fig i the limit depends on the strength of intramolecular interactions between adjacent surface groups, and therefore, on the condition of the bulk solution ie ph, polarity and temperature this nanoscale container feature, originally noted for ����� cheap viagra switch maestro dendrimers by tomalia et al and referred to as unimolecular encapsulation, can be utilized to tailor the encapsulation and release properties of dendrimers in drug delivery applications for example, adding up to a limiting amount of xmmol of either ,dichlorophenoxyacetic acid or aspirin acetylsalicylic acid to mmol of fig periodic properties of ����� dendrimers generations g = , depicting the decreasing distances between surface charges zz the de gennes dense packing appears atg = dendrimers g = display nanoscale container properties, the larger analogues g = display nanoscaffolding properties starburst� carbomethoxyterminated ����� dendrimers generations produced spinlattice relaxation times ti much lower than the values of these guest molecules in solvent without dendrimer the new relaxation times cheap viagra switch maestro decreased for generations , but remained constant for generations to the maximum concentration x varied uniformly from generation to generation on the basis of these maximum concentrations, the guesttohost ratios were shown to be by weight and based on a molar comparison of dendrimer guest carboxylic acidtointerior tertiary nitrogen moieties for generations exceeding the maximum concentration x resulted in the appearance of a second relaxation time, tv, characteristic of the guest molecules in bulk solvent phase dendritic box nano container surfacemodification of g = polypropyleneimine ppi dendrimers with bocprotected amino acids induced dendrimer encapsulation properties by the formation of dense, hydrogenbonded surface shells with solidstate character dendritic box small guestmolecules were captured in such dendrimer interiors and cheap viagra switch maestro were unable to escape even after extensive dialysis the maximum amount of entrapped guest molecules was directly proportional to the shape and size of the guest molecules, as well as to the amount, shape and size of the available internal dendrimer cavities four large guestmolecules ie rose bengal and small guestmolecules ie pnitrobenzoic acid could be simultaneously encapsulated within ppi dendrimers containing four large and twelve smaller cavities remarkably, this dendritic box could be opened under controlled conditions to release either some or all of the entrapped guest molecules for example, partial hydrolysis of the hydrogenbonded bocshell liberated only small guestmolecules, whereas total hydrolysis released all sizes of entrapped molecules although the dendritic box concept cheap viagra switch maestro demonstrates the unique shape dependent cargo space that can be found in certain dendrimers, other parameters have to be considered as well for delivering and releasing therapeutic drugs under physiological conditions from a thermodynamic perspective, free guest molecules ie drugs can be distinguished from those encapsulated or bound in a complex by finite energy barriers related to the ease of entry and departure to the dendrimer cavities if the drug molecule is incompatible with either the dimension or hydrophiliclipophilic character of the dendrimer cavity, a complex might not form, or the guest might only be partially encapsulated within the dendrimer host a hydrophobic drug would be expected to associate with a dendrimer core to achieve maximum cheap viagra switch maestro contact with its hydrophobic domain in addition, the hydrophobic character of this guest molecule would be expected to isolate itself from the dendrimer surface and the interface to the bulk solution to afford minimum contact with polar and aqueous domains ie physiological media notably, the hydrophobic and hydrophilic properties, as well as other noncovalent binding properties of these spatial bindingsites are expected to strongly influence these guesthost relationships analysis of a typical symmetrically branched dendrimer makes it apparent that there are other subtle and yet important parameters that could control the interior space of a dendrimer and influence the guesthost interactions these include components such as branching angles, branching symmetry rotational angles, and the length cheap viagra switch maestro of a repeatunit segment of equal importance are the properties of the core within a homologous ����� dendrimer series, the effect of changing the length scale of the core on dendrimer guesthost properties was studied specifically, a series of polyhydroxysurfaced ����� dendrimers with core molecules differing in length by one carbon atom nhcnnh with n = were synthesized three aromatic carboxylic acids, differing systematically by one aromatic ring benzoic acid, naphthoic acid, anthracene carboxylic acid, were examined as guestmolecule probes two sets of dendrimers, possessing and surface hydroxy groups, were investigated the observed trends can be summarized as follows i in general, all dendritic hosts accommodated larger amounts of the smaller guestmolecule ie molar uptake benzoic cheap viagra switch maestro naphthoic anthracene carboxylic acid this observation was particularly significant for the more congested dendrimer surface having surface ohgroups ii uptake maxima values specific to both the core size and the specific guestprobe were noted this observation might be related to the combination of shape and lipophilicity manifested by the guest probe, iii a decrease in the molar uptake was measured for all probes as the core was enhanced beyond an ideal dimension ie carbons it is therefore obvious that both core size and surface congestion dramatically affect the cargospace of the dendrimer host furthermore, it is apparent that size and shape of the guest probe can significantly affect the maximum loading as a function of cheap viagra switch maestro core size finally, it should also be noted that for the dendrimers g = oh and g = oh, the guest probes had desirable release properties from the host as a function of time, when redissolved in water performing these same experiments using a dendrimer with more densely packed surface groups ie g = with surface ohgroups appeared to produce dendritic box behavior although guest molecules could be encapsulated within the core, the release from the host was delayed as determined by analysis after extensive dialysis structureproperty relationships in dendritic encapsulation have been studied extensively, mainly using photoactive and redox active model dendrimers to gain a better understanding of the structural effects that cores and branches cheap viagra switch maestro have on encapsulation dendrophanes and dendroclefts specific binding of guest molecules to the dendrimer core can affect the loading capacity by enhancing specific interactions between the core and guest ie hydrophobic and polar interactions dendrimers specifically tailored to bind hydrophobic guests to the core have been created by diederich and coworkers and coined dendrophanes these watersoluble dendrophanes are built around a cyclophane core, and can bind aromatic compounds, presumably via pp interactions dendrophanes were shown to be excellent carriers of steroids the same group synthesized dendrimers tailored to bind more polar bioactive compounds to the core, coined dendroclefts, in another approach, the surface amines of ����� dendrimers were modified with trishydroxymethylaminomethane tris to create watersoluble cheap viagra switch maestro dendrimers capable of binding carboxylic aromatic, antibacterial compounds, which could be released by lowering the ph an alternative approach to creating dendritic hosts with highly selective guest recognition utilized the principle of molecular imprinting a dendrimer consisting of a porphyrin core and a surface containing terminal double bonds was polymerized into a polydendritic network subsequently, the baselabile ester bonds between cores and dendritic wedges were cleaved, releasing the porphyrin core from the dendritic polymer this polymer was capable of selectively binding porphyrins with association constants of x s m very recently, an impressive approach has been presented, using tandem mass spectrometry, ie the combination of electro spray ionization esi and collisioninduced dissociation cid mass spectrometers connected cheap viagra switch maestro in series, to investigate the dynamic behavior of hostguest dendrimer complexes this approach offers the potential to provide better insights into these constructs dendrimers in drug delivery dendrimers have been utilized to carry a variety of small molecule pharmaceuticals with the purpose to enhance their solubility and therefore bioavailability, and to utilize the passive and active targeting properties of dendrimers, either through the enhanced permeability and retention epr effect or specific targeting ligands some aspects of dendrimers in drug delivery have been reviewed recently, in the following, selected examples of important drug delivery aspects will be presented cisplatin fig chemical structures of the platinum drugs cisplatin platinolu, carboplatin paraplatin�, and oxaliplatin eloxatin � encapsulation of cheap viagra switch maestro the wellknown anticancer drug cisplatin within ����� dendrimers gives complexes that exhibit slower release, higher accumulation in solid tumors, and lower toxicity compared with free cisplatin, cisplatin is an antitumor drug that exerts its effects by forming stable dnacisplatin complexes through intrastrand crosslinks, resulting in an alteration of the dna structure that prevents replication and activates cell repair mechanisms the cell detects defective dna and initiates apoptosis cisplatin is effective in treating several cancers such as ovarian, head and neck, and lung cancers, as well as melanomas, lymphomas, osteosarcomas, bladder, cervical, bronchogenic, and oropharyngeal carcinomas unfortunately, cisplatin has many adverse side effects to the body, the most important being nephrotoxicity and cytotoxicity to noncancerous tissue, because cheap viagra switch maestro of the nonselective interaction between cisplatin and dna in addition, the therapeutic effect of cisplatin is limited by its poor water solubility mgml, low lipophilicity, and the development of resistance to cisplatin drugs although numerous cisplatin derivatives have undergone preclinical and clinical testing, only cisplatin and its derivatives carboplatin and oxaliplatin have been approved for routine clinical use fig preliminary studies gave cisplatin loadings of wt for ����� dendrimers generation size nm mw kda in comparison, the cisplatin loading of linear polyamidoamines and linear nhydroxypropyl methacry lamide hpma mw kda was found to be wt and wt, respectively hpmacisplatin complexes are currently in clinical trials the cisplatindendrimer complex could be visualized by atomic force microscopy cheap viagra switch maestro afm carbon nanotip as shown in fig fig afm images of cisplatindendrimer complexes at left arid rtm right magnification table auc value jig ptml blood or xg ptorgan over hours micedata point organcisplatincisplatindendrimer complex tumor blood liver kidney the tumor activity of the cisplatindendrimer formulation was studied using bf cells these cells were injected into � mice subcutaneously sc to provide a solid tumor model after approximately days, when the tumors had developed to a mean area of mm, the animals were injected iv with a single dose of either cisplatin or cisplatindendrimer complex mgkg cisplatin for both formulations at certain time points within hours, animals were culled and blood and tissue samples were taken compared cheap viagra switch maestro with cisplatin alone, the cisplatindendrimer complex was found to accumulate preferentially in the tumor site relatively quickly after the injection the tumor area under the curve auc for the complex was times higher than that of free cisplatin, while that in the kidney only increased times, and accumulation in the liver was reduced table i another recent study revealed a sufficient stability of cisplatindendrimer complexes, with a release of cisplatin over the first hours, and an additional release within horns in vivo animal efficacy of the platinate was demonstrated using bf tumor cells that are subcutaneous implanted into mice the tumor was allowed to grow for days prior to treatment with two doses of drug cheap viagra switch maestro on day and day , providing equal cisplatin mgkg doses in both the dendrimer cisplatin complex and free cisplatin a tumor weight reduction of above that observed for the free drug was found in this study silver salts the encapsulation of silver salts within ����� dendrimers produced conjugates, exhibiting slow silver release rates and antimicrobial activity against various gram positive bacteria ����� dendrimers, generation four with ethylenediamine eda core and trishydroxymethylamidomethane tris ohsurface and generation five, eda core with carboxylate coo surface, were used silver containing ����� complexes were prepared by adding aqueous solutions of the dendrimers to the calculated amount of silver acetate powder although cfcooag is hardly soluble in water, it quickly dissolved in the cheap viagra switch maestro ����� solutions this enhancement is due to the combined action of the silver carboxylate salt formation andor to the complex formation with the internal dendrimer nitrogens this procedure resulted in slightly yellow dendrimercomplexsalt solutions that very slowly photolyzed when exposed to light, into dark brown, metallic silver, containing dendrimer silver nanocomposite solutions final sample concentrations were confirmed by atomic absorption spectroscopy for antimicrobial testing, the standard agar overlay method was used in this test, dendrimersilver compounds were examined for diffusible antimicrobial activity by placing a iol sample of each solution onto a mm filter paper disk and applying the disk to a dilute population of the test organisms, staphylococcus aureus, pseudomonas aeruginosa, and escherichia coli cheap viagra switch maestro the silverdendrimer complexes displayed antimicrobial activity, comparable to or better than those of silver nitrate solutions interestingly, increased antimicrobial activity was observed with dendrimer carboxylate salts, which was attributed to the very high local concentration carboxylate groups around a nm diameter sphere of nanoscopic size silver composite particles that are accessible for microorganisms the antimicrobial activity was smaller when internal silver complexes were applied instead of silver adducts to the surface, indicating that the accessibility of the silver is an important factor adriamycin, methotrexate, and fluorouracil the anticancer drugs, adriamycin and methotrexate, were encapsulated into generations and ����� dendrimers which had polyethylene glycol monomethyl ether chains with molecular weights of and da attached to their surfaces cheap viagra switch maestro via urethane bonds fig the encapsulation efficiency was dependent on the peg chain length and the size of the dendrimer, with the highest encapsulation efficiencies on average, adriamycin molecules and methotrexate molecules per dendrimer found for the g = ����� terminated with peg chains the drug release from this dendrimer was sustained at low ionic strength, again reflecting peg chain length and dendrimer size, but fast in isotonic solution in a related study, it was reported that the surface coverage of ����� dendrimers with chjoh och � �� hji ��� fig above structures of anticancer drugs adriamycin left and methotrexate right below schematic presentations of the encapsulation of methotrexate left and fluorouracil right into ����� dendrimers ���?