Multifunctionalization of Dendrimers through Orthogonal Transformations

Goyal, Poorva; Yoon, Kunsang; Weck, Marcus

doi:10.1002/chem.200700129

Cited by 39 publications

(45 citation statements)

References 89 publications

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“…Multifunctional dendrons were synthesized from dendron 14 [31] containing a nitro group at the focal point, six protected acids and one free acid group as described in Scheme 6.…”

Section: H T U N G T R E N N U N G (Ch 2 ) 5 àCooh (8) B) Dyeà a C Hmentioning

confidence: 99%

“…[25][26][27][28][29] Our research group has been developing synthetic strategies for the synthesis of new drug delivery systems based on well-defined multifunctional dendrons and dendri-A C H T U N G T R E N N U N G mers. [30][31][32][33] We were very intrigued by the above-described aminocyanine dyes as potential imaging agents for our multifunctional dendrimer-based delivery system for applications in theranostics. [34][35][36][37][38][39][40][41][42][43] Orthogonality between functional groups is crucial to the synthesis and functionalization of such complex structures, [44] thus, our attention was focused on the derivatization of the NIR dyes with functional groups suitable for orthogonal chemistry.…”

Section: Introductionmentioning

confidence: 99%

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Combining Aminocyanine Dyes with Polyamide Dendrons: A Promising Strategy for Imaging in the Near‐Infrared Region

Ornelas

Lodescar

Durandin

et al. 2011

Chemistry A European J

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Cyanine dyes are known for their fluorescence in the near-IR (NIR) region, which is desirable for biological applications. We report the synthesis of a series of aminocyanine dyes containing terminal functional groups such as acid, azide, and cyclooctyne groups for further functionalization through, for example, click chemistry. These aminocyanine dyes can be attached to polyfunctional dendrons by copper-catalyzed azide alkyne cycloaddition (CuAAC), strain-promoted azide alkyne cycloaddition (SPAAC), peptide coupling, or direct S(NR)1 reactions. The resulting dendron-dye conjugates were obtained in high yields and displayed high chemical stability and photostability. The optical properties of the new compounds were studied by UV/Vis and fluorescence spectroscopy. All compounds show large Stokes shifts and strong fluorescence in the NIR region with high quantum yields, which are optimal properties for in vivo optical imaging.

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“…Multifunctional dendrons were synthesized from dendron 14 [31] containing a nitro group at the focal point, six protected acids and one free acid group as described in Scheme 6.…”

Section: H T U N G T R E N N U N G (Ch 2 ) 5 àCooh (8) B) Dyeà a C Hmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combining Aminocyanine Dyes with Polyamide Dendrons: A Promising Strategy for Imaging in the Near‐Infrared Region

Ornelas

Lodescar

Durandin

et al. 2011

Chemistry A European J

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“…These systems include PAMAM dendrons, 24 dendrimer with single orthogonal modification sites, 25,26 and gold nanoparticles with precise numbers of ligands. 12,13,27,28 …”

Section: New Platform Designsmentioning

confidence: 99%

Heterogeneous Ligand–Nanoparticle Distributions: A Major Obstacle to Scientific Understanding and Commercial Translation

2011

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CONSPECTUS Nanoparticles conjugated with functional ligands are expected to have a major impact in medicine, photonics, sensing, and nanoarchitecture design. One major obstacle to realizing the promise of these materials, however, is the difficulty in controlling the ligand/nanoparticle ratio. This obstacle can be segmented into three key areas: First, many system designs have failed to account for the true heterogeneity of ligand/nanoparticle ratios that compose each material. Second, the field's accepted level of characterization of ligand-nanoparticle materials is deficient as it does not provide an accurate definition of material composition that is necessary to both understand the material-property relationships as well as to monitor the consistency of the material. In particular, many characterization assays only determine the mean ligand/nanoparticle ratio and do not provide the number and relative amount of the different ligand/nanoparticle ratios that compose a material. Third, some synthetic approaches that are presently in use may not produce consistent material as they are sensitive to reaction kinetics, and the synthetic history of the nanoparticle. In this account we describe the recent advances that we have made in understanding the material composition of ligand-nanoparticle systems. Our work has been enabled by a model system using poly(amidoamine) dendrimers and two small molecule ligands. Using reverse phase high-pressure liquid chromatography (HPLC) we have successfully resolved and quantified the relative amount of each ligand/dendrimer ratio present. This type of information is rare for the entire field of ligand-nanoparticle materials because most analytical techniques have been unable to identify the components in the distribution. Our experimental data indicates that the actual distribution of ligand-nanoparticle components is much more heterogeneous than commonly assumed. The mean ligand/nanoparticle ratio that is so often the only information known about a material is insufficient. This is because the mean does not provide information on the diversity of components in the material and often does not describe the most common component (the mode). Additionally, our experimental data has provided examples of material batches with the same mean ligand/nanoparticle ratio and very different distributions. This discrepancy indicates that the mean cannot be used as the sole metric to assess the reproducibility of a system. We further found that distribution profiles can be highly sensitive to the synthetic history of the starting material as well as slight changes in reaction conditions. We have incorporated the lessons from our experimental data into new systems designs to provide improved control over the ligand/nanoparticle ratios.

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“…Unfortunately, no protocol for separating these populations has been published. New developments in dendrimer synthesis aim to bypass issues of distributions completely through orthogonal coupling chemistry 52. One might imagine that future dendritic platforms having enhanced monodispersity with an optimal number of targeting and therapeutic ligands for any given application.…”

Section: Targeted Toxicitymentioning

confidence: 99%

Understanding specific and nonspecific toxicities: a requirement for the development of dendrimer‐based pharmaceuticals

McNerny¹,

Leroueil²,

Baker

2010

WIREs Nanomed Nanobiotechnol

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Dendrimer conjugates for pharmaceutical development are capable of enhancing the local delivery of cytotoxic drugs. The ability to conjugate different targeting ligands to the dendrimer allows for the cytotoxic drug to be focused at the intended target cell while minimizing collateral damage in normal cells. Dendrimers offer several advantages over other polymer conjugates by creating a better defined, more monodisperse therapeutic scaffold. Toxicity from the dendrimer, targeted and nonspecific, is not only dependent upon the number of targeting and therapeutic ligands conjugated, but can be influenced by the repeating building blocks that grow the dendrimer, the dendrimer generation, as well as the surface termination.The narrow therapeutic index of many cytotoxic therapeutics, including doxorubicin, vincristine, cyclophophamide, and paclitaxel, often limits their effectiveness as they must be delivered in suboptimal dosages to prevent side effects in the patient. 1 To remedy this problem, targeted scaffolds can be used to deliver the drug the desired location in an increased, local concentration. As a result, the drug is effective only where it is needed and the undesired side toxicities are diminished. Examples of drug-targeting systems include nanoparticles, liposomes, micelles, linear polymers, branched polymers, and dendrimers. 2 Dendrimer-based platforms have achieved attention for use in pharmaceutical applications.3 -13 Similar to other polymeric carriers, dendrimers can be synthesized to avoid structural toxicity and immunogenicity. However, the unique branched structure of the dendrimer allows for the platform to overcome several significant challenges faced in the development of other polymeric carriers. Many polymers are highly heterogeneous, making characterization and batch reproducibility inherently difficult. Therapeutics with multiple drug or imaging moieties conjugated to a carry are heterogeneous populations that become more disperse as more functionalities are added. These problems often lead to unintended variations in biological activity, because the structural platform is not well understood and is difficult to reproduce. In contrast, the controlled synthesis and growth of dendrimers results in exceptionally low degrees of dispersity [polydispersity index (PDI) <1.1] 14, 15 with well-defined numbers of terminal groups for the conjugation of functional molecules, allowing for improved reproducibility. The dendrimer's ability to mimic the size, solubility, and shape of human proteins makes the

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Multifunctionalization of Dendrimers through Orthogonal Transformations

Cited by 39 publications

References 89 publications

Combining Aminocyanine Dyes with Polyamide Dendrons: A Promising Strategy for Imaging in the Near‐Infrared Region

Combining Aminocyanine Dyes with Polyamide Dendrons: A Promising Strategy for Imaging in the Near‐Infrared Region

Heterogeneous Ligand–Nanoparticle Distributions: A Major Obstacle to Scientific Understanding and Commercial Translation

Understanding specific and nonspecific toxicities: a requirement for the development of dendrimer‐based pharmaceuticals

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