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Synthesis of dendrimers and drug-dendrimer conjugates for drug ..

Binding and conformation of dendrimer-based drug delivery systems: a molecular dynamics study[J].

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Journal of Drug Targeting - Taylor & Francis

When the microglial cells were incubated with FITC-labeled dendrimers, the fluorescence intensity has increased by up to two orders of magnitude during the first two hours (). The significant increase in fluorescence intensity observed within 15 minutes of incubation (an order of magnitude) suggests that the uptake of the dendrimer is rapid. The fluorescence intensity increased another order of magnitude from 15 minutes to 2 hours, which demonstrates that the microglial cells taken up the dendrimer rapidly, presumably by fluid-phase endocytosis, as seen in other cells [,,,]. The results suggest that treatment with dendrimer conjugates can effectively deliver very high extent of their payloads effectively into the cytoplasm within couple of hours. Therefore, in vitro efficacy of conjugates should be high even at shorter treatment time periods, since the high GSH levels in the cells should promote rapid release of the drug.

Design, synthesis, and biological functionality of a dendrimer-based modular drug delivery platform

N2 - A modular dendrimer-based drug delivery platform was designed to improve upon existing limitations in single dendrimer systems. Using this modular strategy, a biologically active platform containing receptor mediated targeting and fluorescence imaging modules was synthesized by coupling a folic acid (FA) conjugated dendrimer with a fluorescein isothiocyanate (FITC) conjugated dendrimer. The two different dendrimer modules were coupled via the 1,3-dipolar cycloaddition reaction ("click" chemistry) between an alkyne moiety on the surface of the first dendrimer and an azide moiety on the second dendrimer. Two simplified model systems were also synthesized to develop appropriate "click" reaction conditions and aid in spectroscopic assignments. Conjugates were characterized by 1H NMR spectroscopy and NOESY. The FA-FITC modular platform was evaluated in vitro with a human epithelial cancer cell line (KB) and found to specifically target the overexpressed folic acid receptor.

Downloads - Drug Discovery Today

AB - A modular dendrimer-based drug delivery platform was designed to improve upon existing limitations in single dendrimer systems. Using this modular strategy, a biologically active platform containing receptor mediated targeting and fluorescence imaging modules was synthesized by coupling a folic acid (FA) conjugated dendrimer with a fluorescein isothiocyanate (FITC) conjugated dendrimer. The two different dendrimer modules were coupled via the 1,3-dipolar cycloaddition reaction ("click" chemistry) between an alkyne moiety on the surface of the first dendrimer and an azide moiety on the second dendrimer. Two simplified model systems were also synthesized to develop appropriate "click" reaction conditions and aid in spectroscopic assignments. Conjugates were characterized by 1H NMR spectroscopy and NOESY. The FA-FITC modular platform was evaluated in vitro with a human epithelial cancer cell line (KB) and found to specifically target the overexpressed folic acid receptor.

Mechanisms of Drug Delivery: Dendrimers are particularly attractive as they offer a high drug-loading capacity. Two methods of dendrimer drug delivery are encapsulation of drugs and dendrimer – drug conjugates.

Glycodendrimers: versatile tools for nanotechnology

Noncovalent Encapsulation of Drugs / Host – Guest Relation: Encapsulation of drugs uses the satiric bulk of the exterior of the dendrimer or Interactions between the dendrimer and drug to trap the drug inside the dendrimer Maciejewski introduced the concept of encapsulating guest molecules into special, egg-shell-like structures. Such a system can be used to encapsulate drugs and provide controlled delivery. For example, in early studies, DNA was complexed with PAMAM dendrimers for gene delivery applications, and hydrophobic drugs and dye molecules were incorporated into various dendrimer cores. An advantage of using dendritic unimolecular micelles rather than conventional polymeric micelles is that the micellar structure is maintained at all concentrations because the hydrophobic segments are covalently connected.

A modular dendrimer-based drug delivery platform was designed to improve upon existing limitations in single dendrimer systems. Using this modular strategy, a biologically active platform containing receptor mediated targeting and fluorescence imaging modules was synthesized by coupling a folic acid (FA) conjugated dendrimer with a fluorescein isothiocyanate (FITC) conjugated dendrimer. The two different dendrimer modules were coupled via the 1,3-dipolar cycloaddition reaction ("click" chemistry) between an alkyne moiety on the surface of the first dendrimer and an azide moiety on the second dendrimer. Two simplified model systems were also synthesized to develop appropriate "click" reaction conditions and aid in spectroscopic assignments. Conjugates were characterized by 1H NMR spectroscopy and NOESY. The FA-FITC modular platform was evaluated in vitro with a human epithelial cancer cell line (KB) and found to specifically target the overexpressed folic acid receptor.

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Molecules, an international, peer-reviewed Open Access journal

Surface modification of dendrimers: In order to increase water solubility, biocompatibility and to reduce toxicity, it is necessary to change the surface of the dendrimers. Now a day, considerable effort has been dedicated to the preparation of dendrimers that are designed to be highly biocompatible and water soluble. In addition, some dendrimers have been designed to be biodegradable, e.g., polylysine 15. Dendrimers having carbohydrate moiety at core or periphery have been widely explored and are emerging as promising immunological tools because of their multivalent binding capacity 16,17 prepared different polyester dendrimers incorporating monomers such as glycerol, succinic acid, phenylalanine, etc. Bhadra et al 18 synthesized PEGylated dendritic nano carrier for the delivery of fluorouracil. The PEGylated dendrimer has shown to increase drug loading but reduced drug release and hemolytic toxicity of dendrimers 19 Majoros studied the nature of the acetylation reaction and reported a method for the preparation of an acylated macromolecule, which can serve as a scaffold for complex dendrimeric structures. Acetylated G5 PAMAM dendrimer represents a more compact structure than the nonacetylated G5 PAMAM dendrimer. In Ref 20 the enhancement of gene transfer activity mediated by mannosylated dendrimer/alpha cyclodextrin activity conjugate has been studied. Jevprasesphant et al. prepared lauryl-dendrimer conjugates to enhance transepithelial transport and reduce cytotoxicity 21.

Current Progress in Gene Delivery Technology Based …

Dendrimer drug conjugates: Drug molecules can be either chemically conjugated to the dendrimer surface or physically encased inside a dendrimer core. For chemical conjugations, a good coupling efficiency may be achieved if functional groups are activated prior to coupling. Hydroxyl (OH), carboxyl (COOH), primary amine (NH 2), thiol (SH) and guanidino are commonly found functional groups in drug molecules and polymers. Hydroxyl groups can be converted to active intermediates that favor nucleophilic reactions. For example, coupling hydroxyl groups with primary amine groups causes primary amine groups to form secondary amines or stable carbamate bonds. Amides are relatively stable in basic, acidic and enzymatic conditions.33. PAMAM dendrimers form conjugates with 5FU, which are water soluble and releases free 5FU slowly on hydrolysis of the conjugate, thereby reducing the toxicity34.

How to cite this article: Jin L, Zeng X, Liu M, Deng Y, He N

Dendrimers can be used as coating agents to protect or deliver drugs to specific sites in the body or as time-release vehicles for biologically active agents. Well defined and macromolecular structure of dendrimer offers the polyvalent characteristic. Through polyvalent interactions with receptors and binding sites, dendrimers may be designed to achieve higher activity than small molecules. In addition, dendrimers may be constructed and modified to have longer duration of action, reduced side effects and other beneficial effects compared with currently available pharmaceuticals. Branched poly (l-glutamic acid) chains were centered on PAMAM dendrimers to create new biodegradable polymers with improved biodistribution and targeting ability. These constructs were surface-terminated with poly (ethylene glycol) chains to enhance their biocompatibility and folic acid receptors to introduce cell-specific targeting35.

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