DOI: 10.1002/chem.201003495 Degradable Dual pH- and Temperature-Responsive Photoluminescent Dendrimers Youqing Shen,* [a, b] Xinpeng Ma, [b] Bo Zhang, [b] Zhuxian Zhou, [b] Qihang Sun, [b] Erlei Jin, [b] Meihua Sui, [a] Jianbin Tang, [a] Jinqiang Wang, [a] and Maohong Fan [b] Introduction Pathological tissues frequently have abnormal local pH or temperature. For instance, the grade of a tumors malignan- cy correlates with its temperature elevation over that of normal tissues. A grade-2 tumor was found to be 1.68 8C warmer than normal tissue. [1] Solid tumors also have a de- creased extracellular pH. [2] Responsiveness to pH or temper- ature has thus been extensively explored for bioinspired functional systems, [3, 4] such as triggered drug release. [5] In particular, dendrimers responsive to these stimuli are envis- aged as ideal biodelivery materials due to their unique prop- erties, which include monodispersity, globular layered archi- tectures, and multivalent peripheries. [6, 7] For example, poly- ACHTUNGTRENNUNGamidoamide (PAMAM) dendrimers undergo conformation- al changes without swelling in response to changes in solu- tion pH. [8] A gadolinium complex conjugated to a dendrimer has been found to display pH-dependent relaxivi- ty in magnetic resonance imaging, this parameter varying from 10.8 mm 1 s 1 per Gd 3 + ion at pH 9 to 24.0 mm 1 s 1 per Gd 3 + ion at pH 6. [9, 10] Moreover, it has been reported that N-isopropylacrylamide (NIPAM)-bearing dendrimers show marked differences in their transition enthalpies, hydropho- bicities, and sensitivities to urea compared with the corre- sponding linear polymers. [11] PAMAM dendrimers have been shown to be capable of carrying and releasing two types of drugs in a controlled manner. [12] Therefore, stimuli- responsive dendrimers offer a unique platform for many ap- plications, [6, 13] particularly biomedical engineering in devel- oping intelligent devices that are able to sense biosignals or microenvironments, [14] such as tumor-sensitive contrast agents, [9, 15] tumor-targeted drug release carriers, [16, 17] and gene delivery carriers. [18] Dual responses to both temperature and pH offer two pa- rameters for manipulating nanocarriers so as to achieve better targeting and efficacy in complicated microenviron- ments [19] or for other functions such as triggered re- lease. [4, 20, 21] Current pH- or temperature-sensitive dendrim- ers are generally made from PAMAM-based dendrimers decorated with appropriate responsive moieties [7, 11, 22] as used in linear polymers, which include acid-sensitive poly- acids [16, 23] and polybases, [24, 25] temperature-responsive alkyla- mides [21, 26] and oligoethylene glycols, [27] or both if responses to both stimuli are required. [4, 20, 21, 28] These dendrimers and responsive moieties are, however, not biodegradable, raising problems were they to be used for parenteral biodelivery. Biodegradable dendrimers, such as polyester dendrimers, are most attractive for such applications [29] because they can Abstract: Poly(b-aminoester) dendrim- ers have been prepared. These systems represent the first degradable dual pH- and temperature-responsive dendrim- ers displaying photoluminescence. The pH/temperature sensitivities are inter- related; the lower critical solution tem- perature of the dendrimer decreases as the pH of the solution is increased. The sensitivities are mainly due to phase changes of the surface groups with changes in pH or temperature. These dual-responsive dendrimers are very useful in drug delivery. They may be loaded with a hydrophobic drug at low temperature without using organic solvents. The loaded drug is released very slowly and steadily at 37 8C and physiological pH, but can be quickly released at acidic pH, for example the lysosomal pH (pH 4–5), for intracellu- lar drug release. These dendrimers also display strong photoluminescence, which can be exploited for monitoring drug loading and release. Thus, poly(b- aminoester) dendrimers constitute ideal drug carriers since their thermal sensitivity allows the loading of drugs without using organic solvents, their pH sensitivity permits fast intracellular drug release, and their photolumines- cence provides a means of monitoring drug loading and release. Keywords: dendrimers · drug deliv- ery · photoluminescence · pH re- sponse · polyesters · temperature response [a] Prof. Y. Shen, Prof. M. Sui, Prof. J. Tang, J. Wang Center for Bionanoengineering and State Key Laboratory of Chemical Engineering Department of Chemical and Biochemical Engineering Zhejiang University, Hangzhou, 310027 (P.R. China) Fax: (+ 86) 571-87953993 E-mail : shenyq@zju.edu.cn [b] Prof. Y. Shen, X. Ma, B. Zhang, Z. Zhou, Q. Sun, E. Jin, Prof. M. Fan Department of Chemical and Petroleum Engineering University of Wyoming, Laramie, WY 82071 (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201003495: Titration curves of the G 4 -NH 2 and G 4 -NMe 2 dendrimers; structure of a control dendri- mer without amine groups. Chem. Eur. J. 2011, 17, 5319 – 5326  2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 5319 FULL PAPER