Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their molecular weight and chemical composition, thereby allowing predictable tuning of their biocompatibility and pharmacokinetics. Advances in our understanding of the role of molecular weight and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors. Before such products can reach the market, however, the field must not only address the cost of manufacture and quality control of pharmaceutical-grade materials, but also assess the long-term human and environmental health consequences of dendrimer exposure in vivo.

Designing dendrimers for biological applications.

Dendrimers and dendritic polymers in drug delivery.

Dendron-mediated self-assembly, disassembly, and self-organization of complex systems have been investigated. The most ideal building blocks would need to display shape persistence in solution and in the solid state, since only this feature provides access to the use of complementary methods of structural analysis. Most supramolecular dendrimers are chiral even when they are constructed from nonchiral building blocks and are equipped with mechanisms that amplify chirality. This poses additional challenges associated with the understanding of the structural origin of chirality in different supramolecular structures through combinations of structural analysis methods. While many supramolecular structures assembled from dendrimers and dendrons resemble some of the related morphologies generated from block-copolymers, they are much more complex and are not determined by the volume ratio between the dissimilar parts of the molecule.

Dendron-Mediated Self-Assembly, Disassembly, and Self-Organization of Complex Systems

https://www.cell.com/trends/biotechnology/pdf/S0167-7799(08)00140-6.pdf

Multifunctional nanoparticles – properties and prospects for their use in human medicine

Effects of nanomaterial physicochemical properties on in vivo toxicity

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery.

An orthogonal, convergent route for the introduction of substoichiometric numbers of latent surface sites into dendrimers based on melamine is used to prepare targets that display one or two Boc-protected amines on the periphery. Asymmetry is the result of the stepwise incorporation of functionalized and unfunctionalized dendrons onto the triazine cores, a highly selective process due to the different reactivities of the substituted triazines. The routes to the dendrons rely on iterative reactions of the growing dendrons with triazine cores and diamine linkers. p-Aminobenzylamine is used as a linking group to avoid functional group interconversions or protecting group manipulations. Addition of the benzylamine group to the monochlorotriazine of the dendron proceeds cleanly leaving a less reactive aniline for subsequent reaction with trichlorotriazine. The routes to these targets proceed in 5 or 6 linear steps (11 or 12 total steps) in 40% overall yield. The unique surface sites can be deprotected and subj...

Orthogonal, convergent syntheses of dendrimers based on melamine with one or two unique surface sites for manipulation.

The rate of thiol-disulfide exchange of dansyl groups mediated by dithiothreitol depends on the structure of the dendrimer. In general, the rate of exchange decreases as the size of the dendrimer increases. Dendrimers with disulfides attached near the core undergo exchange more slowly than dendrimers with disulfides near the periphery. Exchange is a bimolecular (noncooperative) process between dansyl-linked disulfides and dithiothreitol. No evidence for intramolecular macrocylization (cooperative) exchange is observed. Mass spectrometry is used to follow exchange in two dendrimers, providing qualitative and quantitative information about this process. Mathematical models suggest that the rates for exchange for all disulfides of a dendrimer are similar, but increase as the exchange reaction progresses.

Evaluation of multivalent dendrimers based on melamine: kinetics of thiol-disulfide exchange depends on the structure of the dendrimer.

A small library of dendrimers based on triazines was prepared by varying the surface and interior linking groups to study the relationship between structure and the ability of some of these dendrimers to gel in acidified organic solvents including chloroform, methylene chloride, and benzene. Convergent, divergent, and semiconvergent routes yielded eight molecules comprising p-aminobenzylamine or piperazine linking groups and piperidine or butylamine surface groups. Dendrimers that incorporate interior and surface groups capable of hydrogen bonding (p-aminobenzylamine or butylamine) gel at lower concentrations than those groups that offer no hydrogen-bonding protons (piperazine or piperidine). In some cases, these latter molecules do not form gels to the limit of solubility. Studies with competitive solvents corroborate hydrogen bonding, but neither IR nor NMR spectroscopy reveals signals that substantiate this hypothesis. TEM studies show fibers. Studies of these systems at concentrations below that requi...

Structure−Activity Relationships in Dendrimers Based on Triazines: Gelation Depends on Choice of Linking and Surface Groups

Three criteria are evaluated to assess the potential of a dendrimer based on triazines, 1, for use as a vehicle for drug delivery. These criteria are: (1) its ability to solubilize small hydrophobic guests as measured spectrophotometrically; (2) its ability to deliver a drug in vitro as evaluated using a gene reporter assay; and (3) its in vivo toxicity in mice as determined by autopsy and screens of liver and kidney function. Vehicle 1 solubilizes pyrene to a similar extent to dendrimers based on poly(arylether)s, 4, encapsulating approximately 0.2 molecules of pyrene per dendrimer. This activity is approximately 10-fold greater than that of the more polar poly(propyleneimine) and poly(amidoamine) dendrimers, 2 and 3. Gas-phase computational models reveal that both 1 and 4 have cores that are accessible to solvent, suggesting that these dendrimers can occupy much greater volumes than 2 and 3 whose cores are confined toward the interior of the structure. Electrostatic potential maps can be used to rationa...

Wen Zhang

Papers

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery.

Orthogonal, convergent syntheses of dendrimers based on melamine with one or two unique surface sites for manipulation.

Evaluation of multivalent dendrimers based on melamine: kinetics of thiol-disulfide exchange depends on the structure of the dendrimer.

Structure−Activity Relationships in Dendrimers Based on Triazines: Gelation Depends on Choice of Linking and Surface Groups

Triazine Dendrimers for Drug Delivery: Evaluation of Solubilization Properties, Activity in Cell Culture, and In Vivo Toxicity of a Candidate Vehicle