Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups

Changsuk Lee, Su Tang Lo, Jongdoo Lim, Viviana C P Da Costa, Saleh Ramezani, Orhan K. Öz, Giovanni M. Pavan, Onofrio Annunziata, Xiankai Sun, Eric E. Simanek

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkers - dipiperidine trismethylene, piperazine, and aminomethylpiperidine - were used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2′-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by 1H and 13C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5-8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (∼6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg.

Original languageEnglish (US)
Pages (from-to)4452-4461
Number of pages10
JournalMolecular Pharmaceutics
Volume10
Issue number12
DOIs
StatePublished - Dec 2 2013

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Dendrimers
Triazines
Paclitaxel
Neoplasms
Diamines
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Hydrodynamics
Molecular Dynamics Simulation
Disulfides
Hydroxyl Radical
Solubility
Amines
Mass Spectrometry
Prostatic Neoplasms
Spleen
Observation
Lung
Water
Liver

Keywords

  • biodistribution
  • dendrimer
  • disulfide linkage
  • drug delivery
  • molecular dynamics
  • paclitaxel
  • simulation
  • triazine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups. / Lee, Changsuk; Lo, Su Tang; Lim, Jongdoo; Da Costa, Viviana C P; Ramezani, Saleh; Öz, Orhan K.; Pavan, Giovanni M.; Annunziata, Onofrio; Sun, Xiankai; Simanek, Eric E.

In: Molecular Pharmaceutics, Vol. 10, No. 12, 02.12.2013, p. 4452-4461.

Research output: Contribution to journalArticle

Lee, C, Lo, ST, Lim, J, Da Costa, VCP, Ramezani, S, Öz, OK, Pavan, GM, Annunziata, O, Sun, X & Simanek, EE 2013, 'Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups', Molecular Pharmaceutics, vol. 10, no. 12, pp. 4452-4461. https://doi.org/10.1021/mp400290u
Lee, Changsuk ; Lo, Su Tang ; Lim, Jongdoo ; Da Costa, Viviana C P ; Ramezani, Saleh ; Öz, Orhan K. ; Pavan, Giovanni M. ; Annunziata, Onofrio ; Sun, Xiankai ; Simanek, Eric E. / Design, synthesis and biological assessment of a triazine dendrimer with approximately 16 paclitaxel groups and 8 PEG groups. In: Molecular Pharmaceutics. 2013 ; Vol. 10, No. 12. pp. 4452-4461.
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AU - Da Costa, Viviana C P

AU - Ramezani, Saleh

AU - Öz, Orhan K.

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N2 - The synthesis and characterization of a generation three triazine dendrimer that displays a phenolic group at the core for labeling, up to eight 5 kDa PEG chains for solubility, and 16 paclitaxel groups is described. Three different diamine linkers - dipiperidine trismethylene, piperazine, and aminomethylpiperidine - were used within the dendrimer. To generate the desired stoichiometric ratio of 8 PEG chains to 16 paclitaxel groups, a monochlorotriazine was prepared with two paclitaxel groups attached through their 2′-hydroxyls using a linker containing a labile disulfide. This monochlorotriazine was linked to a dichlorotriazine with aminomethylpiperidine. The resulting dichlorotriazine bearing two paclitaxel groups could be reacted with the eight amines of the dendrimer. NMR and MALDI-TOF confirm successful reaction. The eight monochlorotriazines of the resulting material are used as the site for PEGylation affording the desired 2:1 stoichiometry. The target and intermediates were amenable to characterization by 1H and 13C NMR, and mass spectrometry. Analysis revealed that 16 paclitaxel groups were installed along with 5-8 PEG chains. The final construct is 63% PEG, 22% paclitaxel, and 15% triazine dendrimer. Consistent with previous efforts and computational models, 5 kDa PEG groups were essential for making the target water-soluble. Molecular dynamics simulations showed a high degree of hydration of the core, and a radius of gyration of 2.8 ± 0.2 nm. The hydrodynamic radius of the target was found to be 15.8 nm by dynamic light scattering, an observation indicative of aggregation. Drug release studies performed in plasma showed slow and identical release in mouse and rat plasma (8%, respectively). SPECT/CT imaging was used to follow biodistribution and tumor uptake. Using a two component model, the elimination and distribution half-lives were 2.65 h and 38.2 h, respectively. Compared with previous constructs, this dendrimer persists in the vasculature longer (17.33 ± 0.88% ID/g at 48 h postinjection), and showed higher tumor uptake. Low levels of dendrimer were observed in lung, liver, and spleen (∼6% ID/g). Tumor saturation studies of small prostate cancer tumors (PC3) suggest that saturation occurs at a dose between 23.2 mg/kg and 70.9 mg/kg.

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