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

Neerman, Michael F.; Zhang, Wen; Parrish, Alan R.; Simanek, Eric E.

doi:10.1016/j.ijpharm.2004.04.023

Cited by 132 publications

(78 citation statements)

References 14 publications

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“…However, when using piperazine, dimerization of monochlorotriazines was observed under non-ideal reaction conditions that were usually attributed to concentration, rate of addition, ineffective stirring or lack thereof, temperature of addition and the magnitude of stoichiometric excess. 4,[8][9][10][11][12][13][14][15][16][17][18] Reactions with either p-aminobenzylamine or piperazine could be readily followed by NMR. The shift of the benzylic protons on reaction with the monochlorotriazine dendron or the desymmetrization of methylene groups of the piperazine group were diagnostic.…”

Section: Introductionmentioning

confidence: 99%

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Moreno

Simanek

2008

Tetrahedron Letters

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Diamine linkers for the synthesis of dendrimers based on melamine were identified using competition reactions. The relative reactivity of the cyclic monoamines surveyed vary in relative reactivity by 40 times, expanding the previously identified series to an overall relative reactivity range of 320 times. Azetidine is 40 times more reactive than the cyclic, nine-membered ring (C 8 H 17 N), and 320 times more reactive than benzylamine. Reactivity differences are attributed to pKa values and sterics. Incorporating these groups into diamines provides linkers that can be employed in dendrimer synthesis. Specifically, the nucleophilicity of the individual amine groups comprising 3-aminoazetidine, 3-aminopyrrolidine, and 4-aminopiperidine vary by 100 times, 70 times, and 20 times, respectively. These linkers are incorporated into a generation three dendrimer.Our group has invested significant energies in the synthesis of dendrimers based on triazines, also referred to as dendrimers based on melamine deriving from our use of diamine linkers. 1, 2 Our early targets commonly incorporated p-aminobenzylamine because of the significant differences in the reactivity of the amines of this group. That is, during a convergent synthesis, protecting group manipulations and functional group interconversions could be avoided because the benzylic amine would react preferentially (essentially exclusively) with the monochlorotriazine dendron being elaborated. 1,[3][4][5][6][7] The low stability of these aniline derivatives required reasonable, but additional, care on handling. While the use of distilled solvents and inert atmospheres are not uncommon, nor is the requirement for refrigerated storage of intermediates, we recognized that these precautions could impact the broader acceptance of these materials.The low cost and high reactivity of piperazine soon made it a linking diamine of choice for our investigations. However, when using piperazine, dimerization of monochlorotriazines was observed under non-ideal reaction conditions that were usually attributed to concentration, rate of addition, ineffective stirring or lack thereof, temperature of addition and the magnitude of stoichiometric excess. 4,[8][9][10][11][12][13][14][15][16][17][18] Reactions with either p-aminobenzylamine or piperazine could be readily followed by NMR. The shift of the benzylic protons on reaction with the monochlorotriazine dendron or the desymmetrization of methylene groups of the piperazine group were diagnostic. The use of piperazine led to the undesirable formation of dimers, unfortunately. Detecting these dimers by NMR proves difficult due to signal degeneracy between the desired asymmetric monoamine and the symmetric dimer.

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Section: Introductionmentioning

confidence: 99%

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Moreno

Simanek

2008

Tetrahedron Letters

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“…Other studies have shown dendrimers to possess toxic side effects both in vitro and in vivo at high doses, but the effects were minimized by optimizing the dose, chemistry and DNA:dendrimer ratio. [22][23][24] Although not yet tested in human trials, no inflammatory response to the injected dendrimer or to the dendrimer plus ODN-1 was observed in our study at any time using ophthalmological examination. In addition, further examination using immunohistochemistry could not detect an increase in the presence of macrophages, which are related to an inflammatory response mediated by toxicity.…”

Section: Discussionmentioning

confidence: 58%

Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

et al. 2005

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We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (Po0.05) the development of CNV for 4-6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P40.05) in mean severity score at 2 months (2.8670.09), 4 months (2.1570.17) or 6 months (2.770.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases. Gene Therapy (2005) 12, 1544-1550.

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“…Related studies with a cationic dendrimer demonstrated no detectable toxicity in vivo until mice were dosed with 40 mg/kg. 89 Additional recent results are promising because the data suggest that the hepatoxicity of the anticancer drugs methotrexate and 6-mercaptopurine were reduced upon noncovalent encapsulation of these pharmacophores by a melamine-based dendrimer. 90 The accumulation of these data and other animal studies 91 suggests that dendrimers based on melamine have potential for a variety of biomedical applications.…”

Section: Biologically Relevant Moleculesmentioning

confidence: 99%

Dendrimers based on [1,3,5]‐triazines

Steffensen

Hollink

Kuschel

et al. 2006

J. Polym. Sci. A Polym. Chem.

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ABSTRACT:A comprehensive and chronological account of dendrimers based on [1,3,5]-triazines is provided. Synthetic strategies to install the triazine through cycloaddition, cyclotrimerization, and nucleophilic aromatic substitution of cyanuric chloride are discussed.Motivations and applications of these architectures are surveyed, including the preparation of supramolecular assemblies in the solution and solid states and their use in medicines, advanced materials, and separations when anchored to solid supports. V

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

Cited by 132 publications

References 14 publications

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Identification of diamine linkers with differing reactivity and their application in the synthesis of melamine dendrimers

Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

Dendrimers based on [1,3,5]‐triazines

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