All Glycerol Based Thermo-responsive Nanogels for Controlled Drug Delivery

MICHAEL GIULBUDAGIAN; STEFANIE WEDEPOHL; M.A. MOLINA; MARCELO CALDERON

Berlin

Conferencia; 12th International PAT Conference; 2013

Thermo-responsive nanogels are water soluble/dispersible networks that are able to shrink or swell upon a thermal trigger. Their chemical structure is based on linear thermo-responsive polymers connected to cross-linking points, forming a tridimensional lattice. The linear polymers undergo a process of shrinkage or expansion upon a thermal trigger in aqueous environments, providing a responsive modality to the whole network. In such way, they enable the encapsulation of bioactive molecules with high loading capacities and their release at the site of action after an external thermal trigger [1]. In this work we describe a methodology for the synthesis of a thermo-responsive nanogels based on glycerol trough nanoprecipitation polymerization. A systematic study of the conditions and the polymer composition was performed. The sizes, thermo-responsive properties, encapsulation, and release studies were investigated. For the synthesis of the nanogels poly(glycidyl methyl ether-co-ethyl glycidyl ether) (poly(GME-co-EGE)) and hyperbranched polyglycerol (hPG) as crosslinker were copolymerized. Nanogels were prepared by nanoprecipitation while the cross-linking points were generated by (1) copper catalized azide alkyne cycloaddition (CuAAC) [2] or (2) strain promoted azide alkyne cycloaddition (SPAAC) [3]. The size of the particles could be finely tuned from 150 to 400 nm by changing the concentration of the polymers in the synthesis, and the transition temperature could be controlled between 18 to 55°C by varying the composition of the co-polymer and the molecular weight of the thermoresponsive polymer (Fig 1). Figure 1. %Transmitance vs. Temperature for a 1 mg/mL of phosphate buffer solution of different co-polymers. In order to use these nanoparticles as carriers, the encapsulation of different molecules was studied. Due to the synthetic method, hydrophobic molecules could be in situ encapsulated, as for example nile red. On the other hand amphiphilic drugs could be encapsulated post synthesis (doxorubicin, DOXO). Besides, DOXO release was studied and showed temperature responsive release above the cloud point (Fig 2). Figure 2. Cumulative release of DOXO vs. time for GME/EGE 1:1 2.5 kDa at 25°C and 45°C. As a control a non thermo-responsive nanogel was used. These results suggest that these thermoresponsive nanogels are promising as nanocarriers for biomedical applications and therefore cellular experiments are currently ongoing. We gratefully acknowledge financial support from the Bundesministerium für Bildung und Forschung (BMBF) through the NanoMatFutur award (13N12561). [1] M. Asadian-Birjand, A. Sousa-Herves, D. Steinhilber, J.C. Cuggino and M. Calderon, Curr. Med. Chem. 2012; 19, 5029. [2] D. Steinhilber, M. Witting, X. Zhang, M. Staegemann, W. Friess, S. Küchler, and R.Haag, J. Controlled Release. Epub doi: 10.1016/j.jconrel.2012.12.008 [3] J. Dommerholt, S. Schmidt, R. Temming, L. J. A. Hendriks, F. P. J. T. Rutjes, J. C. M. van Hest, D. J. Lefeber, P. Friedl, F. L. van Delft, Angew. Chem. Int. Ed. 2010, 49, 9422.