characteristics, limitations and future perspectives of viral vector transduction curr gene ther studeny m, marini fc, dembinski jl, zompetta c, cabreirahansen m, bekele bn, ciprofloxacin black box warning champlin re and andreeff m mesenchymal stem cells potential precursors for tumor stroma and targeteddelivery vehicles for anticancer agents j natl cancer inst ehtesham m, ciprofloxacin black box warning kabos p, kabosova a, neuman t, black kl and yu js the use of interleukin secreting neural stem cells for the treatment of intracranial glioma ciprofloxacin black box warning cancer res su l, lee r, bonyhadi m, matsuzaki h, forestell s, escaich s, bohnlein e and kaneshima h hematopoietic stem cellbased gene therapy for ciprofloxacin black box warning acquired immunodeficiency syndrome efficient transduction and expression of revmlo in myeloid cells in vivo and in vitro blood sunkomat jn and gaballa ma stem cell therapy ciprofloxacin black box warning in ischemic heart disease car diovasc drug rev huber a, padrun v, deglon n, aebischer p, mohler h and boison d grafts of adenosinereleasing cells ciprofloxacin black box warning suppress seizures in kindling epilepsy proc natl acad sci usa boison d, huber a, padrun v, deglon n, aebischer p and mohler h seizure suppression ciprofloxacin black box warning by adenosinereleasing cells is independent of seizure frequency epilepsia shao j, dehaven j, lamm d, weissman dn, malanga cj, rojanasakul y and ma jk b ciprofloxacin black box warning a cellbased drug delivery system for lung targeting ii therapeutic activities on bf melanoma in mouse lungs drug del alby l and auerbach r differential adhesion of tumor cells to capillary endothelial cells in vitro proc natl acad sci usa cochleates as nanoparticular drug carriers leila zarif introduction in spite of ciprofloxacin black box warning the availability of many nontraditional novel dosage forms, oral route remains the most attractive way for administration of therapeutical materials however, many therapeutic agents, especially ciprofloxacin black box warning the increasing number of biological molecules cannot be taken up by intestine due to their intrinsic impermeability to tissue membranes and the enzymatic degradation through ciprofloxacin black box warning the wall of the gi tract carrier systems that facilitate intestine uptake of these molecules are of major interests in the drug delivery arena moreover, ciprofloxacin black box warning drug delivery systems that provide a route of administration that does not involve injection can improve patient compliance and expand the market for existing, injectable, drugs the factors which are important for the oral efficiency of a vehicle system have been repeatedly summarized in the literature, small particle size, appropriate surface ciprofloxacin black box warning properties, mucoadhesive and targeting moieties, stability, as well as dose are the major factors imparting the efficiency of oral uptake producing formulations of poorly soluble ciprofloxacin black box warning drugs with high bioavailability is an even higher challenge known technologies are nanocrystals and nanoparticles which use the approach of enhancing the bioavailability by a ciprofloxacin black box warning decrease in particle size, resulting in an increase of surface area and subsequently a faster dissolution other technologies such as solid dispersions, polymeric micelles and ciprofloxacin black box warning self emulsifying systems were developed to increase the drug solubility many lipidbased systems were developed to enhance oral bioavailability, examples are lipidbased emulsions & microemulsions solid ciprofloxacin black box warning lipid nanoparticles sln, a high melting point lipids enclosed in a surfactant layer, adequate to enhance the oral bioavailability of poorly absorbed drugs lipid nanocapsules ciprofloxacin black box warning lnc for oral, injectable use and improved bioavailability lipid nanospheres prepared from egg lecithin and soybean, described for their low toxicity and higher efficacy, compared with other delivery systems when incorporating amphotericin b, due to their smaller particle size and lower uptake by reticuloendothelial system, recently, solid lipid microparticles, prepared ciprofloxacin black box warning by the solventinwater emulsiondiffusion technique, were described for the encapsulation and oral delivery of insulin in particular, lipidbased cochleate delivery system appears to provide answers to ciprofloxacin black box warning oral delivery challenges by formulating different kind of molecules, especially hydrophobic ones, and protecting the sensitive and biologically active molecules from harsh environmental conditions in ciprofloxacin black box warning this review, we will focus on cochlea tes nanoparticular drug carrier and will present the main features and the state of the art of this ciprofloxacin black box warning delivery technology cochleates nanoparticles in oral delivery cochleate structure cochleates were first described by dimitrious papahadjopoulos and his coworkers in as precipitates formed by the ciprofloxacin black box warning interaction of negatively charged phos phatidylserine and calcium he named these cylindrical structures cochleate, meaning shell in the greek language because of their rolledup form, and explained the mechanism of cochleates formation by the fusion of negatively charged vesicles induced by the calcium cation fig these cigarlike structures have gained interest ciprofloxacin black box warning as antigen delivery system for vaccine applications more recently cochleates were studied as tools to deliver small molecule drugs a cochleate lipid formulation of amphotericin ciprofloxacin black box warning � has been developed as an oral composition to treat systemic fungal infections other medical and nonmedical applications are also under investigation cochleate preparation which ciprofloxacin black box warning phospholipid and which cation to use cochleates are a phospholipidion precipitates does that mean that cochleate is a structure obtained from precipitation of any phospholipid ciprofloxacin black box warning with any ion as presented in some litterature?, ie a complex of negatively charged phospholipid with any cation or a complex made from a positively charged ciprofloxacin black box warning lipid with any anion � � c � cs fl fusion i ���� {rrirfij ���def fig cochleate cylindrical structure and mechanism of formation adapted from ciprofloxacin black box warning refs and with permission papahadjopoulos has given in this appellation to a rolled phospholipid structure so far, to our knowledge no physicochemical evidence on the ciprofloxacin black box warning obtention of such cigarlike structure from positively charged phospholipid with an anion had been described on the contrary, extensive litterature is available on obtaining these ciprofloxacin black box warning cigarlike structure when negatively charged phospholipid such as phosphos phatidylserine ps had been precipitated with a cation such as calcium other negatively charged phospholipids, such ciprofloxacin black box warning as phosphatidic acid pa or phosphatidyl glycerol derivatives, have been studied as well mixture of negatively charged phospholipids with other lipids can lead to cochleate formation ciprofloxacin black box warning in this case, the cochleate formation depends on the negatively charged lipidother lipid ratio and depends on the nature of the negatively charged lipid in the mixed upid system for example, pa derivatives form cochleate domains after the addition of calcium cation however, when mixed with the corresponding diacylphosphatidyl choline pc and diacylphosphatidylethanolamine pe, it was found that up to mole of pc or pe can be introduced into the cochleate phase of paca, above ciprofloxacin black box warning which a distinct pc rich or perich phase appears other phospholipid derivatives such as galactosphingolipid hydroxy fatty acid cerebroside were reported to form cochleate cylinders by ciprofloxacin black box warning thermal mechanical treatment of glycol suspensions however, the addition of conjugated lipid, such as polyethylene glycollipid conjugates to ps vesicles, inhibited the calciuminduced fusion in ciprofloxacin black box warning general, an additional desired feature of an oral drug delivery system is that the excipient permitting this transport to be classified is generally regarded as ciprofloxacin black box warning safe gras soy phosphatidylserine fits this criteria furthermore, soy ps has been used as a nutrient supplement since early s clinical trials showed that ps ciprofloxacin black box warning may play a role in supporting mental functions in aging brains such as enhancing the memory, improving learning ability, reducing the stress and anxiety cochleates ciprofloxacin black box warning can be made from purified soy phosphatidylserine, which represents an affordable source of raw material a study comparing the purified soy phosphatidylserine psps to nonpurified soy ps npsps has been disclosed in this patent, showing that ps should be present in an amount of at least of the total lipid in order to allow the formation of cochleates the other phospholipids present can be selected either from the anionic group such as phosphatidic acid, phosphatidylglycerol, phosphatidyl inositol or phosphatidylcholine psps cochleates can be loaded with different bioactive materials such as nutritional supplement, vitamins, antiviral, antifungal, small peptides proof of principle of the use of purified soy ps has been achieved using a polyene antifungal agent, amphotericin b the preparation method for amphotericin � cochleates can be either ciprofloxacin black box warning via high phtrapping or film method or by hydrogel method the latter leading to nanocochleates formation the nature of the cation is an important factor ciprofloxacin black box warning in cochleate formation in the precipitation process, divalent cations are preferred to monovalent cations monovalent cations such as na were described to prevent the cochleate ciprofloxacin black box warning formation increases concentration of na ions was shown to interfere with the destabiliza tion effect of ca a critical caps ratio is necessary for the ciprofloxacin black box warning destabilization effect of divalent cations and the formation of cochleate phases the formation of cochleate is easier from small unilamellar vesicles suv however, multilamellar vesicles mlv can also lead to cochleate formation in this case, the first mechanism is a destabilization of the outer bilayer of ps by ca which causes ciprofloxacin black box warning its collapse, leading to a higher access of ca to inner ps bilayers and so forth which molecules can be entrapped in cochleates nanoparticles due ciprofloxacin black box warning to the intrinsic nature of the lipidcontained cochleates, these nanoparticles can encapsulate a variety of molecules of all shapes and sizes preference is given, however, to hydrophobic molecules, for which a need to enhance chemical stability or bioavailability is desired [fig a], amphiphatic molecules which can easily d positively charged ciprofloxacin black box warning moiety ca co co co hydrophobic i molecule ca co co co i amphlpathic molecule i co co co co negatively charged moiety co co ciprofloxacin black box warning ca� sa ipf ff ff ii i i m ca ca ca ca caca ca ca ca ca ca ca ������������������ qg qq ���� co � ciprofloxacin black box warning i � � i co co co ca fig type of molecules which can be encapsulated into lipid based cochleate adapted from ref with permission ciprofloxacin black box warning insert in the membrane bilayers [fig b], negatively charged moiety [fig c] or positively charged moiety [fig d] could be encapsulated in the cochleate nanoparticle structure the nature of the drug influence the percentage of encapsulation hydrophobic drug shows a quantitative encapsulation, whereas less was seen for amphiphatic molecules for ciprofloxacin black box warning instance, doxorubicin which presents hydrophobic regions is a watersoluble drug, has a partition between the bilayers and the external aqueous phase [fig b] as calcium induces ciprofloxacin black box warning dehydration of the interbilayer domains, the amount of water in this region is low, therefore, small hydrophilic molecules will not be suitable for cochleate system ciprofloxacin black box warning multiple ways of preparing cochleates ca ca ca co several processes were developed to obtain cochleates with a nanosize range, with the objective to allow oral delivery, particle size is process dependent when a small nanosized particle is desired, the hydrogel method can be used, based on the use of an aqueousaqueous emulsion system briefly, this method consists of steps the preparation of small size liposomes either by high ph method, or by film method, ciprofloxacin black box warning then the liposomes are mixed with a high viscosity polymer such as dextran the dextranliposome phase is then injected into a second, non miscible, polymer ie ciprofloxacin black box warning peg the calcium was then added and diffused slowly from one phase to another, resulting in the formation of nanocochleates the final step is the ciprofloxacin black box warning washing of the gel these nanosized cochleates showed potential in the oral delivery of drugs electron microscopy and xray crystallography of the nanoparticles show a unique multilayered structure consisting of continuous, solid lipid bilayer sheets, rolled up in a spiral with no internal aqueous space and the localization of amb ciprofloxacin black box warning in the lipid bilayer other preparation techniques are known, eg the trapping method, useful for the encapsulation of hydrophilic and hydrophobic molecules which consist in the preparation of the liposomal suspension containing the drug either in the aqueous space of liposome when hydrophilic or intercalated in between the bilayers when hydrophobic a step of addition of calcium follows, and an aggregate of cochleates are formed the cochleates made by the trapping method present higher aggregation compared ciprofloxacin black box warning with other methods this has been demonstrated using electron microscopy after freezefracture another method was developed for hydrophobic drugs, known as the solvent drip method ciprofloxacin black box warning which consists of preparing a liposomal suspension separately based on soy ps and a hydrophobic or amphipathic cargo moiety solution solvent for hydrophobic drug can ciprofloxacin black box warning be selected from dmso, dmf the solution is then added to liposomal suspension since the solvent is miscible in water, a decrease of the solubility of ciprofloxacin black box warning the cargo moiety is observed, which associates at least in part with the lipidhydrophobic liposomal bilayers the cochleates are then obtained by addition of calcium ciprofloxacin black box warning and the excess solvent is being washed usually, the cochleate formation can be characterized by optical microscopy when they are present in needle form in the micrometer size range in this case, direct observation using a higher magnification can be used when nanocochleate are obtained, optical microscope can be used ciprofloxacin black box warning as an indirect method to assess the formation of cochleate, ie observation of the liposome formation after chelation of the calcium present, by addition of edta ethylene diamine tetraacetate to nanocochleate a more sophisticated method is the electron microscopy after freeze fracture, which allows the observation of the tighted packed bilayers ciprofloxacin black box warning recently, other methods were described using laurdan dodecanoyldimethylamino naphtalene to monitor the cochleate phase formation in this case, the lipid vesicles are labeled with laurdan ciprofloxacin black box warning and the addition of calcium to the laurdan labeled vesicles resulted in a shift in the emission peak maximum of laurdan due to dipolar relaxation, ciprofloxacin black box warning excitation and emission, generalized polarization gpex and gpem indicates the transition from a lc to a rigid and dehydrated cochleate phase cochleates as oral delivery ciprofloxacin black box warning system for antifungal agent, amphotericin � among the drug of choice using nanocochleate delivery system, amphotericin � amb presented all aspects of a good candidate amphotericin ciprofloxacin black box warning � is a hydrophobic drug with poor oral bioavailability this drug had been used for decades in injectable form to treat systemic fungal infections of ciprofloxacin black box warning candida, cryptococcus and aspergillosis species lipid formulations of amphotericin � such as liposomes, lipid complexes, lipid emulsions and colloidal dispersions, were developed with the aim ciprofloxacin black box warning to achieve a higher therapeutic index, these formulations indeed showed enhanced therapeutic index, even though none of these formulations showed ability to deliver amb orally ciprofloxacin black box warning cocheate technology seems to offer the advantage over other delivery systems in providing the effexor xr usual normal dose possibility for the oral delivery of amb oral administration of amphotericin � ciprofloxacin black box warning cochleates camb to healthy mice achieved potentially therapeutic concentrations in key target tissues preclinical studies demonstrate a promising activity of camb in murine models of ciprofloxacin black box warning clinically relevant invasive fungal infections such as disseminated candidiasis, disseminated aspergillosis, and central nervous system cryptococcosis in candidiasis animal model in candida albicans infected murine ciprofloxacin black box warning animal model, amb cochleates showed potential either after intraperitoneal ip or oral po administration after ip administration camb provided protection against c albicans at doses as low as mgkgday, kidney tissues burden showed that camb was more potent than fungizone� at mgkgday and was equivalent to ambisome� at mgkgday fig ciprofloxacin black box warning camb was also effective after oral administration complete eradication of c albicans from the lungs was noticed after po administration at mgkgday these results were comparable ciprofloxacin black box warning to ip fungizone� at mgkgday in aspergillosis animal model oral administration of camb was shown to be protective in a dose dependent manner against systemic ciprofloxacin black box warning infection of aspergillus fumigatus in animals immunosusppressed with cyclophosphamide, in this mouse model, intragastric administration of camb at mgkgday for days resulted in survival, while fungizone at mgkgday ip resulted in survival higher doses of fungizone were lethal to animals s ?st w j t � �� �ft t � � o u � � o� � �� oo� t control atnb dose concentration mgkg fig kidneys tissue burden of infected mice treated with either camb , fungizone ?