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