POSITIVELY CHARGED THERMORESPONSIVE NANOGELS FOR DOXORUBICIN DELIVERY

M.A. MOLINA; MICHAEL GIULBUDAGIAN; MARCELO CALDERON

Berlin

Conferencia; 12th International PAT Conference; 2013

Within the nanoscale carriers, nanogels (NG) are of a particular interest as drug delivery systems. Their properties such as hydrophilicity, flexibility, high water absorptivity, long circulation time in plasma, and biocompatibility make them attractive carriers. Poly(N-isopropylacrylamide) (pNIPAm) nanogels are widely studied because of the simple synthetic pathway and the fact that they possess a volume phase transition temperature (VPTT) in a very narrow temperature range (~32 ºC) [1]. We have developed a methodology to fabricate thermo-responsive NG using NIPAm and hyperbranched polyglycerol (hPG) as a macro-crosslinker [2]. The incorporation of hPG enhanced the water solubility and the biocompatibility of the nanogels. In the present work we evaluate the influence of a positively charged co-monomer into the NIPAm-hPG based nanogels to achieve specific interactions with desired drugs. The synthesis of thermo-responsive nanogels were carried out by radical cross-linking polymerization of NIPAm co-polymerized with (2-Dimethylamino) ethyl methacrylate (DMAEM) and cross-linked with acrylated hPG. Monodispersed nanogel particles were obtained when NIPAm and DMAEM (12%) were copolymerized with 33 wt% hPG. The particles were analyzed by DLS, NMR, FT-IR, and UV spectroscopy. The incorporation of the DMAEM was confirmed by FT-IR spectroscopy. The two strong amide absorption bands at about 1630 cm-1 and 1540 cm-1 are associated to p(NIPAm). Compared to the 33 wt% hPG-(NIPAm) nanogel absorption frequencies, a peak of the ester is determined at 1725-1750 cm-1 in the co-polymer (Fig 1) associated to the DMAEM. Figure 1. FTIR ? spectrum of 33 wt% hPG-p(NIPAm) ( ) and 33 wt% hPG-p(NIPAm-co-DMAEM 12%) ( ) nanogels. DLS measurements showed that the sizes of swollen nanogels increase from 88 nm for the 33% hPG p(NIPAm) nanogel to 170 nm for the 33% hPG p(NIPAm-co-DMAEM 12%) nanogel due to the incorporation of a more hydrophilic monomer. For the same reason, the DMAEM co-polymerization leaded to a dramatic increase in the VPTT from 32°C to 50°C. Strongly depending on the pH, the VPTT has shown to be 45 ºC at pH 8.5 and higher than 50 ºC at pH 7.4. In order to use these particles as anticancer nanocarriers, the encapsulation of doxorubicin (Doxo) in the nanogels was studied (Table 1). Table 1. Encapsulation of Doxo in a 33wt% hPG-p(NIPAm) and b 33 wt% hPG-p(NIPAm-co-DMAEM 12%) nanogels. The loading capacity of the positively charged nanogel is two times bigger than p(NIPAM) nanogels at 48 hs when measured in the high concentration of Doxo solution. This fact can be attributed to the high swelling ratio and the water content of these particles as is probed from the DLS results. These results suggest that the incorporation of a more hydrophilic co-monomer in the nanogels can improve the encapsulation of drugs. Cellular experiments are currently ongoing to prove the efficacy of the drug loaded nanogels. We gratefully acknowledge financial support from the Bundesministerium für Bildung und Forschung (BMBF) through the NanoMatFutur award (13N12561). [1] R. Pelton. Advances in Colloid and Interface Science; 2000, 85, 1. [2] J. C. Cuggino, et al. Soft Matter; 2011, 7, 11259.