goh , and gcooh � ����� dendrimers at ph n = , rsd encapsulation efficiency of eda core ����� dendrimer ? g i �jii rdl jri i id at i� u e ?c o � v a v at l tris leton lithium battery protector sue nh peg pyr ae coona surface functionality fig encapsulation efficiency into famam dendrimers generations with amino nh, polyethyene glycol leton lithium battery protector peg, carbomethoxypyrrolidinone fyr, amidoethanol ae, sodium carboxylate coona, succinamic acid suc, and tris hydroxy me thy ammomethane tris surface leton lithium battery protector groups core and amino surface g = , or ester surface g = at ph , and , the solubility enhancement of nifedipine leton lithium battery protector was higher in the presence of esterterminated dendrimers than their aminoterminated analogues, possessing the same number of surface groups the nifedipine solubility ex pec ted lv increased with the size of the dendrimers for ph , the sequence g g g leton lithium battery protector g g g go was reported in another approach, the nonsteroidal antiinflammatory drug naproxen was covalently attached to unsymmetrical leton lithium battery protector polyarylester dendrimers to prepare a complex with enhanced water solubility of the drug and access for hydrplytic cleavage e t leton lithium battery protector ek k k k concentration mmolecular weight fig aqueous paclitaxel solubility as a function of the polyglycerol dendrimer concentration mean leton lithium battery protector � sd, n = g circle, g triangle, g square, and peg diamond left molecular weight dependency of dendrimers closed leton lithium battery protector circle and peg open circle on the aqueous paclitaxel solubility the concentration of dendrimers and peg was wt reproduced leton lithium battery protector with permission from ref copyright american chemical society of the bond between drug and carrier detailed results on the biological leton lithium battery protector evaluation of these complexes have not been reported the anticancer drug paclitaxel, which is being used to treat metastatic breast and ovarian cancers and kaposis sarcoma, has poor water solubility to enhance its bioavailability, paclitaxel has been encapsulated into polyglycerol dendrimers, resulting in a ,fold improved water solubility compared with the pure drug, which is much higher than that leton lithium battery protector found for peg, a commonly used linear chain cosolvent or hydrotropic agent fig the drug release rate was a function leton lithium battery protector of the dendrimer generation generation ����� dendrimers with hydroxy surface have been utilized to improve the bioavailability of the corticosteroid leton lithium battery protector methylprednisolone, which decreases inflammation by stabilizing leukocyte lysosomal membrane by connecting the drug to the dendrimer using glutaric acid leton lithium battery protector as the spacer, a payload of wt was achieved the drugdendrimer complex was taken up by a human lung epithelial leton lithium battery protector carcinoma cells and mostly localized in the cytosol the complex showed a pharmacological activity comparable to the free drug as leton lithium battery protector measured by the inhibition of the prostaglandin secretion doxorubicin and camptothecin � selfimmolative dendritic prodrugs an exciting new approach to dendritic drug delivery involves the utilization of a drug as a part of the dendritic molecule selfimmolative dendrimers have leton lithium battery protector recently been developed and introduced as a potential platform for a multiprodrug these unique structural dendrimers can release all of their outer branch units through fig mechanism of dimeric prodrug activation by a single enzymatic cleavage reproduced with permission from leton lithium battery protector ref copyright american chemical society a selfimmolative chain fragmentation, initiated by a single cleavage at the den drimers core leton lithium battery protector incorporation of drug molecules as these outer branch units and an enzyme substrate as the trigger can generate a multiprodrug unit that will be activated with a single enzymatic cleavage fig the first generation of dendritic prodrugs with doxorubicin and camptothecin as branch units and retromichael focal trigger, which can be cleaved by the catalytic antibody c, has been reported bioactivation of the dendritic prodrugs was evaluated in cellgrowth inhibition assay with the molt leukemia cell line in the leton lithium battery protector presence and absence of antibody c a remarkable increase in toxicity was observed dependent on the linker molecule, different numbers leton lithium battery protector of drug molecules can be released in one single activation step in a more classical approach to deliver doxorubicin, two polyesterbased dendrimers generation with trisphenolic core were synthesized, one carrying a hydroxy surface, the other a triethylene glycol monomethyl ether leton lithium battery protector surface these dendrimers were compared with a arm polyethylene oxide star polymer, carrying g = dendritic polyester units at leton lithium battery protector the surface the star polymer gave the most promising results regarding cytotoxicity and systemic circulatory halflife hrs therefore, the anticancer drug doxorubicin was covalently bound to this carrier via an acidlabile hydrazone linkage the cytotoxicity of doxorubicin was significantly reduced and the drug was successfully taken up by several cancer cell lines photodynamic therapy pdt and boron neutron capture therapy leton lithium battery protector bnct dendrimers have been used to optimize the antitumor effect in photodynamic therapy pdt and boron neutron capture therapy bnct one of the newest developments in the dendrimer field is their application to photodynamic therapy pdt this cancer treatment involves the administration of a lightactivated photosensitizing moiety that selectively concentrates in diseased tissue subsequent activation of the photosensitizer leads leton lithium battery protector to the generation of reactive oxygen, primarily singlet oxygen, that damages intracellular components such as lipids and amino acid leton lithium battery protector residues through oxidation, ultimately leading to cell death by apoptosis disadvantages of currently used photosensitizers include skin phototoxicity, poor selectivity leton lithium battery protector for tumor tissue, poor water solubility, and difficulties in the treatment of solid tumors because of the impermeability of the leton lithium battery protector skin and tissues to the visible light required to excite the chromophores in one set of studies, dendrimers have been leton lithium battery protector constructed around a light harvesting core ie a porphyrin to reduce the toxicity under nonirradiative conditions dark toxicity and leton lithium battery protector to prevent aggregation, and consequently, selfquenching of the porphyrin cores, these dendrimers have been further encapsulated into micelles for example, leton lithium battery protector polyethylene glycolbpolyaspartic acid and pegbpolyllysine micelles have been studied in this regard these micelles are stable under physiological conditions ph leton lithium battery protector to however, they disintegrate in the acidic intracellular endosomal compartment ph alternatively, the photosensitizer aminolevulinic acid has been attached to the surface of dendrimers and studied as an agent for pdt of tumorigenic keratinocytes photosensitive dyes have been incorporated leton lithium battery protector into dendrimers and utilized in pdt devices for example, uptake, toxicity, and the mechanism of photosensitization of the dye pheophorbide a pheo was compared with its complex with diaminobutane polypropylene imine dab dendrimers in human leukemia cells in vitroi the leton lithium battery protector second therapy, boron neutron capture therapy, is a cancer treatment based on a nuclear capture reaction when b is leton lithium battery protector irradiated with low energy or thermal neutrons, highly energetic �particles and li ions are produced, that are toxic to tumor leton lithium battery protector cells to achieve the desired effects, it is necessary to deliver b to tumor cells at a concentration of at leton lithium battery protector least atoms per cell high levels of boron accumulation in tumor tissue can be achieved by using boronated antibodies that leton lithium battery protector are targeted towards tumor antigens however, this approach can impair the solubility and targeting efficiency of the antibodies one leton lithium battery protector study, involving intratumoral injection of a conjugation between a generation ����� dendrimer carrying boron atoms and cetuximab, a monoclonal antibody leton lithium battery protector specific for the egf receptor, showed that the conjugate was present fig schematic presentation of an eda core g = leton lithium battery protector ����� dendrimer , the boron carrier ������������ , and the targeting ligand folic acid reproduced with permission from ref copyright american chemical society at an almost fold higher concentration in brain tumors than in normal brain tissue to reduce the liver leton lithium battery protector uptake observed for boronated ����� dendrimer conjugates, peg chains were attached onto the dendrimer surface, in addition to the borane leton lithium battery protector clusters, to provide steric shielding as compared with a dendrimer without peg chains, the amount of liver uptake was found leton lithium battery protector to be less for pegconjugated dendrimers with an average of chains of peg but higher for dendrimers with chains leton lithium battery protector of peg folic progene testosterone builder acid moieties were also conjugated to the ends of the peg chains to enhance the uptake of leton lithium battery protector the dendrimers by tumors overexpressing folate receptors although this strategy was successful in enhancing localization of the molecules to tumors in mice bearing jkfbp tumors expressing the folate receptor, it also led to an increase in the uptake of the dendrimers by the liver and kidneys nanoscaffolds for targeting ligands the surface of dendrimers provides an excellent platform for leton lithium battery protector the attachment of cell specific ligands, solubility modifiers, stealth molecules, reducing the interaction with macromolecules from the body defense system, and imaging tags the ability to attach any or all of these molecules in a welldefined and controllable manner onto leton lithium battery protector a robust dendritic surface, clearly differentiates dendrimers from other carriers such as micelles, liposomes, emulsion droplets, and engineered particles folic leton lithium battery protector acid one example of cellspecific dendritic carriers is a dendrimer modified with folic acid the membraneassociated high affinity folate leton lithium battery protector receptor hfr is a folate binding protein that is overexpressed on the surface of a variety of cancer cells, and leton lithium battery protector therefore, folatemodified dendrimers would be expected to internalize into these cells preferentially over normal cells via receptormediated endocytosis folate dendrimer leton lithium battery protector conjugates have been shown to be wellsuited for targeted, cancer specific drug delivery of cytotoxic substances in a very recent study, branched polylglutamic acid chains were centered around ����� dendrimers generations and and polyethylene imine pei cores to create leton lithium battery protector new biodegradable polymers with improved biodistribution and targeting ability these constructs were surfaceterminated with polyethylene glycol chains to enhance their leton lithium battery protector biocompatibility, and folic acid ligands to introduce cell specific targeting cell binding studies have been performed using the epidermal carcinoma leton lithium battery protector cell line, kb carbohydrates in addition to folates, carbohydrates constitute another important class of biological recognition molecules, displaying a leton lithium battery protector wide variety of spatial structures due to their branching possibility and anomericity to achieve sufficiently high binding affinities between simple leton lithium battery protector mono and oligosaccharide ligands and cell membrane receptors, these ligands have to be presented to the receptors in a multivalent leton lithium battery protector or cluster fashion the highly functionalized surface of dendrimers provides an excellent platform for such presentations the design, synthesis, and biomedical use of glycodendrimers, as well as their application in diagnostic and for vaccinations, have been thoroughly reviewed recently leton lithium battery protector for example, the thomsen friedenreich carbohydrate antigen tantigen, jgallagalnac, which has been well documented as an important antigen for the detection and immunotherapy of carcinomas, especially relevant to breast cancer, has been attached to the surface of ����� and other dendrimers an enhanced binding affinity was observed for all glycodendrimers these constructs could have potential in blocking the metastatic sites of invasive tumor cells a series of dendritic cyclodextrin derivatives, bearing multivalent mannosyl ligands, has been prepared and their leton lithium battery protector binding efficiency towards the plant lectin concanavalin a con a and a mammalian mannosespecific cell surface receptor from macrophages has leton lithium battery protector been studied the effects of glycodendritic architecture on binding efficiency, molecular inclusion, lectinbinding properties, and the consequence of complex formation using the anticancer drug docetaxel on biological recognition were investigated di to tetravalent dendritic galabiosides, carrying galalgal moieties on their surfaces, were studied as inhibitors of pathogens based on bacterial species such as e coli and streptococcus suis attachment leton lithium battery protector of dendritic galabiosides onto cell surfaces would be expected to inhibit the attachment of bacteria using the same sugar ligandreceptor leton lithium battery protector interactions the study revealed a clear enhancement of the binding affinity between glycodendrons and cell surfaces, with an increasing number leton lithium battery protector of sugar moieties in a similar approach, glycodendrons carrying two to four jdgalactose moieties on their surface, while the leton lithium battery protector dendron core was connected to a proteindegrading enzyme, were synthesized these glycodendriproteins are expected to attach to the surface of leton lithium battery protector bacteria, allowing the enzyme to degrade the bacterial adhesin, hence rendering the bacteria incapable of attaching to the cell surfaces leton lithium battery protector anionic ����� dendrimers c = were conjugated to dglucosamine and dglucoseamine fisulfate these watersoluble conjugates not only revealed immunomodulatory and leton lithium battery protector antian giogenic properties, but synergistically prevented scar tissue formation after glaucoma filtration surgery in a validated and clinically relevant leton lithium battery protector rabbit study, the long term success rate was increased from to using these d end rimerconjugates antibodies and biotinavidin binding leton lithium battery protector generation ����� dendrimerendrimers with amino surface were conjugated to fluorescein isothio cyan ate as a means to analyze cell binding and internalization two different antibodies, bca and j, which bind tocd and prostatespecific membrane antigen psma respectively, were used as mode!