1 Full Paper Macromolecular Chemistry and Physics wileyonlinelibrary.com © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/macp.201400286 Positively Charged Thermoresponsive Nanogels for Anticancer Drug Delivery Maria Molina, Michael Giulbudagian, Marcelo Calderón* Thermoresponsive nanogels (NGs) are often used as smart nanocarriers for delivering bio- active molecules. Copolymerization of monomers with different functionalities is a well- known technique that enables the tuning of their properties. Here, the synthesis of positively charged thermoresponsive NGs is reported, based on ( N- isopropylacrylamide) (NIPAM) as a thermoresponsive mon- omer, 2-dimethyl(aminoethyl) methacrylate (DMAEM) as a charged comonomer, and dendritic acrylated polyglycerol (dPG) as a macro-crosslinker. The NGs are characterized in terms of size, Z potential, and transition temperature. In order to evaluate its potential for anticancer therapy, the encapsu- lation and release of anticancer drugs such as doxorubicin (DOXO) and methotrexate (MTX) are tested. A high drug loading capacity and release rate make these NGs promising nanocarriers for biomedical applications. Dr. M. Molina, M. Giulbudagian, Prof. M. Calderón Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany E-mail: marcelo.calderon@fu-berlin.de Dr. M. Molina, M. Giulbudagian, Prof. M. Calderón Helmholtz Virtuelles Institut – Multifunctional Biomaterials for Medicine, Helmholtz-Zentrum Geesthacht, Teltow, Germany Beyond a critical temperature, known as the lower crit- ical solution temperature (LCST), the polymer becomes insoluble and collapses into a globular conformation. The existence of LCST is attributed to the disruption of water cages surrounding the NIPAM moieties, which induces the formation of inter- and intramolecular hydrogen bonds between PNIPAM chains. [11] The ability to tune the LCST by introducing suitable comonomers with desired functional properties opens up possibilities for diverse medical applications. [12,13] Among others, introducing pH-responsive modalities is attractive since the pH of the cancer cells is slightly acidic and therefore a synergy with the thermosensi- tivity modality is obtained. [14] 2-Dimethyl(aminoethyl)- methacrylate (DMAEM) is a water-soluble monomer that has been explored as comonomer to introduce pH respon- siveness in thermosensitivity NGs due to the presence of tertiary amine groups, which can be protonated in acidic solutions. The influence of the addition of DMAEM in PNIPAM microgels was investigated by Zha et al. [15–17] They found that the size of the microgels, as well as the LCST, is strongly influenced by the presence of the cati- onic monomer. 1. Introduction Nanogels (NGs) are of particular interest as drug delivery systems. [1,2] Their properties such as hydrophilicity, flex- ibility, high water absorptivity, long circulation time in plasma, and biocompatibility make them attractive nanoscale carriers. [3–6] Poly( N-isopropylacrylamide) (PNIPAM) NGs are widely studied because of their simple synthetic pathway and the fact that they possess a volume phase transition temperature (VPTT) in a very narrow temperature range (≈32 °C). [7–9] As a consequence of change in polymer solu- bility, reversible phase transition occurs, which enables the release of drugs in response to temperature stimuli. [10] Early View Publication; these are NOT the final page numbers, use DOI for citation !! Macromol. Chem. Phys. 2014, DOI: 10.1002/macp.201400286