Abstract
Chemical modifications of the biotin carrier in pretargeted avidin-biotin radionuclide therapy may be of paramount importance for tuning the amount of the radioactivity delivered to cancer cells by labelled biotins. We report here the synthesis of a collection of new synthetic DOTA-constructs bearing two (+)-biotin molecules (bis-biotins), designed for the creation of multimeric Av units (tetramers) bonded to the antibody. All the syntheses were carried out following the solid phase strategy and growing the molecules on a Rink Amide resin. The biotin heads are connected through spacers containing PEG or non-PEG residues. Molecular modelling calculations suggested that the Av cross-linking ability of the bis-biotins depends mainly on the spacers length, with the best results being expected for arms affording distances in the range of 10-25 Å between the biotin carboxylate atoms, in the fully extended conformation. SEC-HPLC MALLS analysis of the products of our Av/bis-biotin reaction mixtures have confirmed this hypothesis. The bis-biotin 16, where the non-PEG linker ensured a distance of 26.7 Å between the biotin moieties, gave about 50% of Av oligomers while the shorter analogue 18 (19.5 Å) afforded 100% of an Av polymer containing about 21 protein units. Remarkably, the solubility of both the bis-biotins, i.e.16 and 18, in aqueous solutions was good and they showed excellent stability against the action of peptidases. This journal is
| Original language | English |
|---|---|
| Pages (from-to) | 3988-4001 |
| Number of pages | 14 |
| Journal | Organic and Biomolecular Chemistry |
| Volume | 13 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Apr 7 2015 |
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ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Organic Chemistry
- Biochemistry
- Medicine(all)
Cite this
Design and solid phase synthesis of new DOTA conjugated (+)-biotin dimers planned to develop molecular weight-tuned avidin oligomers. / Pratesi, Alessandro; Ginanneschi, Mauro; Melani, Fabrizio; Chinol, Marco; Carollo, Angela; Paganelli, Giovanni; Lumini, Marco; Bartoli, Mattia; Frediani, Marco; Rosi, Luca; Petrucci, Giorgio; Messori, Luigi; Papini, Anna Maria.
In: Organic and Biomolecular Chemistry, Vol. 13, No. 13, 07.04.2015, p. 3988-4001.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Design and solid phase synthesis of new DOTA conjugated (+)-biotin dimers planned to develop molecular weight-tuned avidin oligomers
AU - Pratesi, Alessandro
AU - Ginanneschi, Mauro
AU - Melani, Fabrizio
AU - Chinol, Marco
AU - Carollo, Angela
AU - Paganelli, Giovanni
AU - Lumini, Marco
AU - Bartoli, Mattia
AU - Frediani, Marco
AU - Rosi, Luca
AU - Petrucci, Giorgio
AU - Messori, Luigi
AU - Papini, Anna Maria
PY - 2015/4/7
Y1 - 2015/4/7
N2 - Chemical modifications of the biotin carrier in pretargeted avidin-biotin radionuclide therapy may be of paramount importance for tuning the amount of the radioactivity delivered to cancer cells by labelled biotins. We report here the synthesis of a collection of new synthetic DOTA-constructs bearing two (+)-biotin molecules (bis-biotins), designed for the creation of multimeric Av units (tetramers) bonded to the antibody. All the syntheses were carried out following the solid phase strategy and growing the molecules on a Rink Amide resin. The biotin heads are connected through spacers containing PEG or non-PEG residues. Molecular modelling calculations suggested that the Av cross-linking ability of the bis-biotins depends mainly on the spacers length, with the best results being expected for arms affording distances in the range of 10-25 Å between the biotin carboxylate atoms, in the fully extended conformation. SEC-HPLC MALLS analysis of the products of our Av/bis-biotin reaction mixtures have confirmed this hypothesis. The bis-biotin 16, where the non-PEG linker ensured a distance of 26.7 Å between the biotin moieties, gave about 50% of Av oligomers while the shorter analogue 18 (19.5 Å) afforded 100% of an Av polymer containing about 21 protein units. Remarkably, the solubility of both the bis-biotins, i.e.16 and 18, in aqueous solutions was good and they showed excellent stability against the action of peptidases. This journal is
AB - Chemical modifications of the biotin carrier in pretargeted avidin-biotin radionuclide therapy may be of paramount importance for tuning the amount of the radioactivity delivered to cancer cells by labelled biotins. We report here the synthesis of a collection of new synthetic DOTA-constructs bearing two (+)-biotin molecules (bis-biotins), designed for the creation of multimeric Av units (tetramers) bonded to the antibody. All the syntheses were carried out following the solid phase strategy and growing the molecules on a Rink Amide resin. The biotin heads are connected through spacers containing PEG or non-PEG residues. Molecular modelling calculations suggested that the Av cross-linking ability of the bis-biotins depends mainly on the spacers length, with the best results being expected for arms affording distances in the range of 10-25 Å between the biotin carboxylate atoms, in the fully extended conformation. SEC-HPLC MALLS analysis of the products of our Av/bis-biotin reaction mixtures have confirmed this hypothesis. The bis-biotin 16, where the non-PEG linker ensured a distance of 26.7 Å between the biotin moieties, gave about 50% of Av oligomers while the shorter analogue 18 (19.5 Å) afforded 100% of an Av polymer containing about 21 protein units. Remarkably, the solubility of both the bis-biotins, i.e.16 and 18, in aqueous solutions was good and they showed excellent stability against the action of peptidases. This journal is
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UR - http://www.scopus.com/inward/citedby.url?scp=84925340669&partnerID=8YFLogxK
U2 - 10.1039/c4ob02685c
DO - 10.1039/c4ob02685c
M3 - Article
C2 - 25722026
AN - SCOPUS:84925340669
VL - 13
SP - 3988
EP - 4001
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
SN - 1477-0520
IS - 13
ER -