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The key role of the scaffold on the efficiency of dendrimer nanodrugs.

Caminade AM, Fruchon S, Turrin CO, Poupot M, Ouali A, Maraval A, Garzoni M, Maly M, Furer V, Kovalenko V, Majoral JP, Pavan GM, Poupot R - Nat Commun (2015)

Bottom Line: Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs.Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks.This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratoire de Chimie de Coordination du CNRS, UPR 8241, 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France [2] Université de Toulouse, UPS, INP, LCC, F-31077 Toulouse, France.

ABSTRACT
Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.

No MeSH data available.


Related in: MedlinePlus

Equilibrated configurations of the 13 dendrimers and their size, obtained from the MD simulations.(a) Radius of gyration (Rg) of the different dendrimers extracted from the equilibrated phase of the MD simulations in solution, number of azabisphosphonic surface groups (END) and biological efficiency score. Shape analysis: (b) MD equilibrated snapshots of the thirteen dendrimers displaying their shape. Dotted circles are added around the dendrimers to emphasize differences in the displacement of the azabisphosphonic functions around the dendrimers surface (symmetrical or directional molecules).
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f6: Equilibrated configurations of the 13 dendrimers and their size, obtained from the MD simulations.(a) Radius of gyration (Rg) of the different dendrimers extracted from the equilibrated phase of the MD simulations in solution, number of azabisphosphonic surface groups (END) and biological efficiency score. Shape analysis: (b) MD equilibrated snapshots of the thirteen dendrimers displaying their shape. Dotted circles are added around the dendrimers to emphasize differences in the displacement of the azabisphosphonic functions around the dendrimers surface (symmetrical or directional molecules).

Mentions: Molecular modelling was used to understand the striking differences observed in the biological properties. To gain molecular-level information about the dendrimers in the biological conditions, all-atom MD simulations of the 13 dendrimers in solution were carried out at 37 °C in presence of explicit water molecules and NaCl (150 mM). Each molecular system was equilibrated during 200 ns of MD simulation (Supplementary Fig. 1). Different data were extracted from the equilibrated phase MD trajectories. Figure 6a reports the equilibrated size data (that is, the radius of gyration, Rg) for the dendrimers in solution. Comparison of the Rg data with the number of terminal groups indicates that neither the size (generation) of the dendrimers (we used generations 1 and 2), nor the number of terminal functions are exclusively important criteria for the biological activity of each molecule. For instance, the activity of dendrimer 4-G1 (8 terminal functions) is marked ++, as that of dendrimers 2-G1, 3-G1 and 5b-G1 (12 terminal functions); nevertheless, dendrimers 6b-G2, 7b-G2 and 8a-G2 also have 8 terminal functions, but no activation properties towards monocytes.


The key role of the scaffold on the efficiency of dendrimer nanodrugs.

Caminade AM, Fruchon S, Turrin CO, Poupot M, Ouali A, Maraval A, Garzoni M, Maly M, Furer V, Kovalenko V, Majoral JP, Pavan GM, Poupot R - Nat Commun (2015)

Equilibrated configurations of the 13 dendrimers and their size, obtained from the MD simulations.(a) Radius of gyration (Rg) of the different dendrimers extracted from the equilibrated phase of the MD simulations in solution, number of azabisphosphonic surface groups (END) and biological efficiency score. Shape analysis: (b) MD equilibrated snapshots of the thirteen dendrimers displaying their shape. Dotted circles are added around the dendrimers to emphasize differences in the displacement of the azabisphosphonic functions around the dendrimers surface (symmetrical or directional molecules).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4510975&req=5

f6: Equilibrated configurations of the 13 dendrimers and their size, obtained from the MD simulations.(a) Radius of gyration (Rg) of the different dendrimers extracted from the equilibrated phase of the MD simulations in solution, number of azabisphosphonic surface groups (END) and biological efficiency score. Shape analysis: (b) MD equilibrated snapshots of the thirteen dendrimers displaying their shape. Dotted circles are added around the dendrimers to emphasize differences in the displacement of the azabisphosphonic functions around the dendrimers surface (symmetrical or directional molecules).
Mentions: Molecular modelling was used to understand the striking differences observed in the biological properties. To gain molecular-level information about the dendrimers in the biological conditions, all-atom MD simulations of the 13 dendrimers in solution were carried out at 37 °C in presence of explicit water molecules and NaCl (150 mM). Each molecular system was equilibrated during 200 ns of MD simulation (Supplementary Fig. 1). Different data were extracted from the equilibrated phase MD trajectories. Figure 6a reports the equilibrated size data (that is, the radius of gyration, Rg) for the dendrimers in solution. Comparison of the Rg data with the number of terminal groups indicates that neither the size (generation) of the dendrimers (we used generations 1 and 2), nor the number of terminal functions are exclusively important criteria for the biological activity of each molecule. For instance, the activity of dendrimer 4-G1 (8 terminal functions) is marked ++, as that of dendrimers 2-G1, 3-G1 and 5b-G1 (12 terminal functions); nevertheless, dendrimers 6b-G2, 7b-G2 and 8a-G2 also have 8 terminal functions, but no activation properties towards monocytes.

Bottom Line: Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs.Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks.This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratoire de Chimie de Coordination du CNRS, UPR 8241, 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France [2] Université de Toulouse, UPS, INP, LCC, F-31077 Toulouse, France.

ABSTRACT
Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.

No MeSH data available.


Related in: MedlinePlus