Dual-Responsive Controlled Drug Delivery Based on Ionically Assembled Nanoparticles Wei Cui, † Xuemin Lu, † Kun Cui, † Lvye Niu, † Yen Wei, ‡ and Qinghua Lu* ,† † School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, P.R. China ‡ Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China * S Supporting Information ABSTRACT: Ionically assembled nanoparticles (INPs) have been formed from poly(ionic liquid-co-N-isopropylacrylamide) with deoxycholic acid through electrostatic interaction. The structure and properties of the INPs were investigated by using 1 H NMR, Fourier transform infrared (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS), and so on. Due to pH-responsive deoxycholic acid (pK a = 6.2) and thermo responsive N-isopropylacrylamide included in the ionic complex, the INPs exhibit highly pH and thermal dual-responsive properties. The potential practical applications as drug delivery carriers were demonstrated using doxorubicin (DOX) as a model drug. With a lower pH (pH 5.2) and higher temperature (above 37 °C), structural collapse of the INPs occurred as well as release of DOX owing to protonated DA departure from the INPs and a lower LCST (lower critical solution temperature) at the pathological conditions. The result shows that 80% of DOX molecules were released from INPs within 48 h at pH 5.2, 43 °C, but only 30% of the drug was released within 48 h at 37 °C and pH 7.4. Moreover, drug-loaded INPs exhibit an inhibitory effect on cell growth. 1. INTRODUCTION In the past decade, stimuli-responsive materials (nanoparticles, micelles, vesicles, gels, etc.) have received much attention as drug nanocarriers because they can offer the advantages of improving the therapeutic activity of the drug, reducing general drug toxicity, and decreasing drug dosage. 1-4 Rapid growth of malignancy cells can cause a temperature increase and a pH decrease in its microenvironment, providing a handle for pathological cells treatment with controlled drug release. Such a concept has fueled research toward the development of thermo-, pH-, or dual-responsive polymeric nanocarriers. 5-8 Among them, dual responsive polymeric nanoparticle is a much more attractive topic and received wide and intensive interest due to its potential advantage in intelligently distinguishing normal and pathological cells, so achieving much better release and control compared to monoresponsive nanocarriers. A series of smart nanoparticles were prepared based on the copolymer of thermo responsive poly(N-isopropylacrylamide) (PNI- PAAM) and pH sensitive moiety. For example, Zhang et al. synthesized poly(N-isopropylacrylamide-co-acrylic acid)-poly- (caprolactone) nanoparticles for anticancer drug delivery. 6 It was found that these nanoparticles deformed at body temperature under conditions of slightly acidic pH (pH 6.9), which triggered the release of the loaded anticancer drug. Similarly, Liu et al. developed poly (N,N-diethylacrylamide-co- methacrylic acid) microspheres with well-defined temperature- sensitive cores and pH-sensitive shells for site-specific drug delivery in the intestine. 9 In this research, an alkaline pH of the medium led to swelling of the microspheres and an accelerated drug release rate. However, for most of the present dual- responsive systems, pH response resulted from the acidic pH environment reducing the lower critical solution temperature (LCST) of copolymers. However, acidic pH did not directly cause dissociation of nanoparticles. On the other hand, a complicated procedure was also included in preparation of such system. For further improving therapeutic efficacy of controlled Received: April 23, 2012 Revised: May 19, 2012 Published: May 24, 2012 Article pubs.acs.org/Langmuir © 2012 American Chemical Society 9413 dx.doi.org/10.1021/la3016436 | Langmuir 2012, 28, 9413-9420