- Email: [email protected]
Facile preparation and drug delivery behavior of novel dextran-based nanogels conjugated with doxorubicin via a pH-labile bond
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
about 200 nm with good monodispersity. Its drug loading content was 1250 mg/g (drug/carrier) and a long-term drug release of 150 h was obtained. The successful conjugation of folic acid in the copolymer shell provides for the targeting ability to cancer cells in which the folate receptor is over expressed. T2-weighted phantom images revealed that the nanocomposites still have strong signal intensity even at a low concentration. In summary, a biocompatible, water-soluble and magnetic nanocomposite for anti-cancer drug delivery was prepared via a simple self-assembly process.
e67
scanning electron microscopy (SEM) revealed that PLGA/SN-38 NPs were uniform in size and exhibit a fairly narrow size distribution (150–310 nm) (Fig. 1, A). PLGA NP dispersions with a concentration 0.75 mg/ml were non-toxic for A549/DDP cells after 24 h incubation as established with the WST-1 assay. The IC50 values (nM) of free SN-38 and PLGA/SN-38 NPs were 167.2 and 85.5, respectively. The cell death induced by PLGA/SN-38 NPs was up to 2.0-times higher than that of free SN-38. To certify that drug intracellular accumulation induced by PLGA NPs is associated with P-gp, ATP depletion and UIC2 monoclonal antibody (mAb) blocking were carried out. The mean fluorescence intensity (MFI) increased in A549/DDP cells from 11.0 ± 0.813 (without NaN3, an ATPases inhibitor) to 29.1 ± 1.30 (with NaN3, 10 mM) (Fig. 1, Ba, Bb). MFI was respectively 12.8 ± 0.676 and 31.3 ± 2.18 (p b 0.05) when PLGA NPs were incubated without or with UIC2 mAb for 1 h (Fig. 1, Bc, Bd). The results indicated that PLGA NPs might be effective in regulating the P-gp efflux pump. In conclusion, our DDS had higher anticancer efficacy with reversal MDR by modulating P-gp on A549/DDP cell line in vitro.
Scheme 1. Schematic depiction of the structure of HAMAFA-b-DBAM-coated IBU@HMS@C18@SPIONPs and controlled release by degradation under weakly acidic conditions.
Keywords: Controlled drug release, pH-sensitive, Magnetic nanocomposite, Self-assembly Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 20902065, 21076134, 21176164), the Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Reference [1] D.Y. Chen, X.W. Xia, H.W. Gu, Q.F. Xu, J.F. Ge, Y.G. Li, N.J. Li, J.M. Lu, pHresponsive polymeric carrier encapsulated magnetic nanoparticles for cancer targeted imaging and delivery, J. Mater. Chem. 21 (2011) 12682–12690.
doi:10.1016/j.jconrel.2013.08.137
PLGA nanoparticles containing SN-38 for reversing multiple drug resistance of A549/DDP cells Ying Wang, Miao Guo, Yu Lu, Liying Ding, Shuqin Yu Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing 210046, China E-mail address: [email protected] (S. Yu). Nanotechnology has brought expectations for the design of drug delivery systems (DDS) to solve multiple drug resistance (MDR) related to P-glycoprotein (P-gp). Some excipients have been used as P-gp modulators for reversal MDR to avoid the toxicity of P-gp inhibitors in DDS [1]. 7-Ethyl-10-hydroxy-camptothecin (SN-38) is the substrate of P-gp and an active metabolite which is 1000-fold more effective than its prodrug irinotecan. Unfortunately, the metabolic conversion of irinotecan to SN-38 is only 10% in vivo [2]. To reduce the serious side effects brought by a large dosage of irinotecan, and to improve the effect of SN-38, we prepared novel SN-38 loaded PLGA nanoparticles (NPs) named PLGA/SN-38 NPs. PLGA/SN-38 NPs were prepared by the oil-in-water (O/W) solvent evaporation method. Dynamic light scattering (DLS) and
Fig. 1. (A) The SEM photograph; (B) the fluorescence photograph: Ba: without NaN3, Bb: with NaN3, Bc: without UIC2 mAb, and Bd: with UIC2 mAb.
Keywords: Drug delivery system, PLGA, SN-38, Multiple drug resistance, P-glycoprotein Acknowledgements This work was supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. References [1] X. Xie, Q. Tao, Y. Zou, F. Zhang, M. Guo, Y. Wang, H. Wang, Q. Zhou, S. Yu, PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms, J. Agric. Food Chem. 59 (2011) 9280–9289. [2] Y. Kawato, M. Aonuma, Y. Hirota, H. Kuga, K. Sato, Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11, Cancer Res. 51 (1991) 4187–4191.
doi:10.1016/j.jconrel.2013.08.138
Facile preparation and drug delivery behavior of novel dextran-based nanogels conjugated with doxorubicin via a pH-labile bond Shuyan Zhoua, Hongjing Doua,⁎, Zhaofeng Zhangb, Yuqing Jinb, Zunli Shenb, Kang Suna,⁎ a The State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China b Department of Plastic and Reconstructive, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China E-mail addresses: [email protected] (S. Zhou), [email protected] (H. Dou), [email protected] (K. Sun). Nanogels have long been regarded as promising drug delivery system (DDS) for their biocompatibility, stability, and especially stimuli responsiveness. Doxorubicin (DOX) is a widely used chemotherapeutic agent in cancer treatment, but its application is strongly restricted due
e68
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
to its short biological half-life and nonspecific distribution. It is well known that the pH of tumor tissues is lower than the pH of normal tissues. Furthermore many tumors over-express folic acid receptors [1]. On this basis we designed and successfully prepared a smart drug delivery system from dextran-based nanogels. We synthesized monodisperse poly(methyl acrylate) grafted dextran nanogels (DM NGs) with a hydrodynamic diameter of about 100 nm by a one-pot approach developed by our group [2], and further conjugated DOX through pH-labile hydrazone bonds by reacting DM NGs with excessive amounts of hydrazinium hydroxide and then DOX (DMDOX NGs) [3]. Folic acid (FA) was also conjugated to the nanogel through amide condensation to offer active targeting of nanogels (DMDOX FNGs) to solid tumors. The structure of all reaction products was confirmed by 1H-NMR. Both Dex-PMA-DOX NGs with or without FA showed a pH dependent release of DOX with 60% release at pH 5.0 and only 20% at pH 7.4 after 60 h, which also confirmed the successful linkage of DOX through a hydrazone bond. MTT assays with HeLa cells showed little toxicity of the DM NGs, while DMDOX FNGs were very effective in delivering DOX into the nucleus of HeLa cells as shown by fluorescence microscopy after co-incubating DMDOX FNGs with HeLa cells for 24 h. Owing to their FA active targeting, passive targeting of EPR (enhanced permeation and retention) effect, and pH responsive drug release, DMDOX FNGs are very promising as new DDS for anti-cancer therapeutics.
Regenerated silk fibroin (RSF) derived from Bombyx mori silk is one of the non-bioactive proteins that has been widely studied in biomedical and pharmaceutical fields [1]. In the past decade, significant effort has been directed to develop RSF nanospheres as drug carries. However, most studies only use model drugs and the preparation processes for the drug carrier are complicated. In our previous work, we developed a simple, mild, and clean method, which was a combination of ethanol addition and freezing RSF solution, to form RSF nanospheres with controllable size from 100 to 1000 nm [2]. By such a method, we successfully prepared hydrophobic anticancer drug paclitaxel loaded RSF nanospheres [3]. In this research, we selected a hydrophilic anticancer drug floxuridine to investigate the possibility to produce another kind of drug-loaded RSF nanospheres (Fig. 1a). Both TEM and dynamic light scattering showed that the floxuridine-loaded RSF nanospheres were uniform without apparent aggregation and that the size was controllable. The maximum drug loading is about 7.8% and the release time is more than 50 h. Cellular uptake experiments confirmed that the floxuridine-loaded RSF nanospheres were adsorbed and endocytosed by HeLa cell (Fig. 1b). Moreover, the floxuridine-loaded RSF nanospheres showed almost the same capability of cellular growth inhibition as the pristine floxuridine solution. The present research indicates that our method can be used to prepare RSF nanospheres with both hydrophilic and hydrophobic anticancer drugs, and that the resulting size-controllable (ranging from 200 to 500 nm) anticancer drug nanocarriers have a great potential for lymphatic chemotherapy in clinical applications.
Scheme 1. One-pot synthesis of DM NGs and further conjugation of FA and DOX, and DMDOX FNGs could efficiently deliver DOX into HeLa cells after a 24 h incubation.
Keywords: Dextran-based nanogel, Hydrazone, Doxorubicin, HeLa cell
Fig. 1. Scheme of the preparation process of floxuridine-loaded RSF nanospheres (a) and microscope image of HeLa cells incubated with FITC-labeled floxuridine-loaded RSF nanospheres (b).
Acknowledgements This work was supported by the National Natural Science Foundation of China (Nos. 20904032, 21174082).
Keywords: Natural polymer, Floxuridine, Green preparation process, Lymphatic chemotherapy
References [1] F. Danhier, O. Feron, V. Préat, To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery, J. Control. Release 148 (2010) 135–146. [2] M.H. Tang, H.J. Dou, K. Sun, One-step synthesis of dextran-based stable nanoparticles assisted by self-assembly, Polymer 47 (2006) 728–734. [3] L. Zhou, R. Cheng, H.Q. Tao, S.B. Ma, W.W. Guo, F.H. Meng, H.Y. Liu, Z. Liu, Z.Y. Zhong, Endosomal pH-activatable poly(ethylene oxide)-graft-doxorubicin prodrugs: synthesis, drug release, and biodistribution in tumor-bearing mice, Biomacromolecules 12 (2011) 1460–1467.
doi:10.1016/j.jconrel.2013.08.139
Acknowledgements This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education, MOE of China (No. 20110071110008) References [1] G.H. Altman, F. Diaz, C. Jakuba, T. Calabro, R.L. Horan, J.S. Chen, H. Lu, J. Richmond, D.L. Kaplan, Silk-based biomaterials, Biomaterials 24 (2003) 401–416. [2] Z.B. Cao, X. Chen, J.R. Yao, L. Huang, Z.Z. Shao, The preparation of regenerated silk fibroin microspheres, Soft Matter 3 (2007) 910–915. [3] M.J. Chen, Z.Z. Shao, X. Chen, Paclitaxel-loaded silk fibroin nanospheres, J. Biomed. Mater. Res. A 100A (2012) 203–210.
doi:10.1016/j.jconrel.2013.08.140 Size-controllable anticancer drug loaded silk fibroin nanospheres Shuying Yua,b, Sheng Chenc,⁎, Mengjie Chena,b, Xin Chena,b,⁎ a State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China b Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China c Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China E-mail addresses: [email protected] (S. Yu), [email protected] (X. Chen).
Controlled release of ibuprofen from PCLA–PEG–PCLA based thermogels Ting Lia, Liang Chena, Tianyuan Cia, Lin Yua,b, Jiandong Dinga,b,⁎ a Key Laboratory of Molecular Engineering of Polymers of Ministry of Education, Department of Macromolecular Science, Advanced Materials Laboratory, Fudan University, Shanghai 200433, China b Key Laboratory of Smart Drug Delivery of Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai 201203, China E-mail address: [email protected] (J. Ding).
about 200 nm with good monodispersity. Its drug loading content was 1250 mg/g (drug/carrier) and a long-term drug release of 150 h was obtained. The successful conjugation of folic acid in the copolymer shell provides for the targeting ability to cancer cells in which the folate receptor is over expressed. T2-weighted phantom images revealed that the nanocomposites still have strong signal intensity even at a low concentration. In summary, a biocompatible, water-soluble and magnetic nanocomposite for anti-cancer drug delivery was prepared via a simple self-assembly process.
e67
scanning electron microscopy (SEM) revealed that PLGA/SN-38 NPs were uniform in size and exhibit a fairly narrow size distribution (150–310 nm) (Fig. 1, A). PLGA NP dispersions with a concentration 0.75 mg/ml were non-toxic for A549/DDP cells after 24 h incubation as established with the WST-1 assay. The IC50 values (nM) of free SN-38 and PLGA/SN-38 NPs were 167.2 and 85.5, respectively. The cell death induced by PLGA/SN-38 NPs was up to 2.0-times higher than that of free SN-38. To certify that drug intracellular accumulation induced by PLGA NPs is associated with P-gp, ATP depletion and UIC2 monoclonal antibody (mAb) blocking were carried out. The mean fluorescence intensity (MFI) increased in A549/DDP cells from 11.0 ± 0.813 (without NaN3, an ATPases inhibitor) to 29.1 ± 1.30 (with NaN3, 10 mM) (Fig. 1, Ba, Bb). MFI was respectively 12.8 ± 0.676 and 31.3 ± 2.18 (p b 0.05) when PLGA NPs were incubated without or with UIC2 mAb for 1 h (Fig. 1, Bc, Bd). The results indicated that PLGA NPs might be effective in regulating the P-gp efflux pump. In conclusion, our DDS had higher anticancer efficacy with reversal MDR by modulating P-gp on A549/DDP cell line in vitro.
Scheme 1. Schematic depiction of the structure of HAMAFA-b-DBAM-coated IBU@HMS@C18@SPIONPs and controlled release by degradation under weakly acidic conditions.
Keywords: Controlled drug release, pH-sensitive, Magnetic nanocomposite, Self-assembly Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 20902065, 21076134, 21176164), the Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Reference [1] D.Y. Chen, X.W. Xia, H.W. Gu, Q.F. Xu, J.F. Ge, Y.G. Li, N.J. Li, J.M. Lu, pHresponsive polymeric carrier encapsulated magnetic nanoparticles for cancer targeted imaging and delivery, J. Mater. Chem. 21 (2011) 12682–12690.
doi:10.1016/j.jconrel.2013.08.137
PLGA nanoparticles containing SN-38 for reversing multiple drug resistance of A549/DDP cells Ying Wang, Miao Guo, Yu Lu, Liying Ding, Shuqin Yu Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing 210046, China E-mail address: [email protected] (S. Yu). Nanotechnology has brought expectations for the design of drug delivery systems (DDS) to solve multiple drug resistance (MDR) related to P-glycoprotein (P-gp). Some excipients have been used as P-gp modulators for reversal MDR to avoid the toxicity of P-gp inhibitors in DDS [1]. 7-Ethyl-10-hydroxy-camptothecin (SN-38) is the substrate of P-gp and an active metabolite which is 1000-fold more effective than its prodrug irinotecan. Unfortunately, the metabolic conversion of irinotecan to SN-38 is only 10% in vivo [2]. To reduce the serious side effects brought by a large dosage of irinotecan, and to improve the effect of SN-38, we prepared novel SN-38 loaded PLGA nanoparticles (NPs) named PLGA/SN-38 NPs. PLGA/SN-38 NPs were prepared by the oil-in-water (O/W) solvent evaporation method. Dynamic light scattering (DLS) and
Fig. 1. (A) The SEM photograph; (B) the fluorescence photograph: Ba: without NaN3, Bb: with NaN3, Bc: without UIC2 mAb, and Bd: with UIC2 mAb.
Keywords: Drug delivery system, PLGA, SN-38, Multiple drug resistance, P-glycoprotein Acknowledgements This work was supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. References [1] X. Xie, Q. Tao, Y. Zou, F. Zhang, M. Guo, Y. Wang, H. Wang, Q. Zhou, S. Yu, PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms, J. Agric. Food Chem. 59 (2011) 9280–9289. [2] Y. Kawato, M. Aonuma, Y. Hirota, H. Kuga, K. Sato, Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11, Cancer Res. 51 (1991) 4187–4191.
doi:10.1016/j.jconrel.2013.08.138
Facile preparation and drug delivery behavior of novel dextran-based nanogels conjugated with doxorubicin via a pH-labile bond Shuyan Zhoua, Hongjing Doua,⁎, Zhaofeng Zhangb, Yuqing Jinb, Zunli Shenb, Kang Suna,⁎ a The State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China b Department of Plastic and Reconstructive, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China E-mail addresses: [email protected] (S. Zhou), [email protected] (H. Dou), [email protected] (K. Sun). Nanogels have long been regarded as promising drug delivery system (DDS) for their biocompatibility, stability, and especially stimuli responsiveness. Doxorubicin (DOX) is a widely used chemotherapeutic agent in cancer treatment, but its application is strongly restricted due
e68
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
to its short biological half-life and nonspecific distribution. It is well known that the pH of tumor tissues is lower than the pH of normal tissues. Furthermore many tumors over-express folic acid receptors [1]. On this basis we designed and successfully prepared a smart drug delivery system from dextran-based nanogels. We synthesized monodisperse poly(methyl acrylate) grafted dextran nanogels (DM NGs) with a hydrodynamic diameter of about 100 nm by a one-pot approach developed by our group [2], and further conjugated DOX through pH-labile hydrazone bonds by reacting DM NGs with excessive amounts of hydrazinium hydroxide and then DOX (DMDOX NGs) [3]. Folic acid (FA) was also conjugated to the nanogel through amide condensation to offer active targeting of nanogels (DMDOX FNGs) to solid tumors. The structure of all reaction products was confirmed by 1H-NMR. Both Dex-PMA-DOX NGs with or without FA showed a pH dependent release of DOX with 60% release at pH 5.0 and only 20% at pH 7.4 after 60 h, which also confirmed the successful linkage of DOX through a hydrazone bond. MTT assays with HeLa cells showed little toxicity of the DM NGs, while DMDOX FNGs were very effective in delivering DOX into the nucleus of HeLa cells as shown by fluorescence microscopy after co-incubating DMDOX FNGs with HeLa cells for 24 h. Owing to their FA active targeting, passive targeting of EPR (enhanced permeation and retention) effect, and pH responsive drug release, DMDOX FNGs are very promising as new DDS for anti-cancer therapeutics.
Regenerated silk fibroin (RSF) derived from Bombyx mori silk is one of the non-bioactive proteins that has been widely studied in biomedical and pharmaceutical fields [1]. In the past decade, significant effort has been directed to develop RSF nanospheres as drug carries. However, most studies only use model drugs and the preparation processes for the drug carrier are complicated. In our previous work, we developed a simple, mild, and clean method, which was a combination of ethanol addition and freezing RSF solution, to form RSF nanospheres with controllable size from 100 to 1000 nm [2]. By such a method, we successfully prepared hydrophobic anticancer drug paclitaxel loaded RSF nanospheres [3]. In this research, we selected a hydrophilic anticancer drug floxuridine to investigate the possibility to produce another kind of drug-loaded RSF nanospheres (Fig. 1a). Both TEM and dynamic light scattering showed that the floxuridine-loaded RSF nanospheres were uniform without apparent aggregation and that the size was controllable. The maximum drug loading is about 7.8% and the release time is more than 50 h. Cellular uptake experiments confirmed that the floxuridine-loaded RSF nanospheres were adsorbed and endocytosed by HeLa cell (Fig. 1b). Moreover, the floxuridine-loaded RSF nanospheres showed almost the same capability of cellular growth inhibition as the pristine floxuridine solution. The present research indicates that our method can be used to prepare RSF nanospheres with both hydrophilic and hydrophobic anticancer drugs, and that the resulting size-controllable (ranging from 200 to 500 nm) anticancer drug nanocarriers have a great potential for lymphatic chemotherapy in clinical applications.
Scheme 1. One-pot synthesis of DM NGs and further conjugation of FA and DOX, and DMDOX FNGs could efficiently deliver DOX into HeLa cells after a 24 h incubation.
Keywords: Dextran-based nanogel, Hydrazone, Doxorubicin, HeLa cell
Fig. 1. Scheme of the preparation process of floxuridine-loaded RSF nanospheres (a) and microscope image of HeLa cells incubated with FITC-labeled floxuridine-loaded RSF nanospheres (b).
Acknowledgements This work was supported by the National Natural Science Foundation of China (Nos. 20904032, 21174082).
Keywords: Natural polymer, Floxuridine, Green preparation process, Lymphatic chemotherapy
References [1] F. Danhier, O. Feron, V. Préat, To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery, J. Control. Release 148 (2010) 135–146. [2] M.H. Tang, H.J. Dou, K. Sun, One-step synthesis of dextran-based stable nanoparticles assisted by self-assembly, Polymer 47 (2006) 728–734. [3] L. Zhou, R. Cheng, H.Q. Tao, S.B. Ma, W.W. Guo, F.H. Meng, H.Y. Liu, Z. Liu, Z.Y. Zhong, Endosomal pH-activatable poly(ethylene oxide)-graft-doxorubicin prodrugs: synthesis, drug release, and biodistribution in tumor-bearing mice, Biomacromolecules 12 (2011) 1460–1467.
doi:10.1016/j.jconrel.2013.08.139
Acknowledgements This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education, MOE of China (No. 20110071110008) References [1] G.H. Altman, F. Diaz, C. Jakuba, T. Calabro, R.L. Horan, J.S. Chen, H. Lu, J. Richmond, D.L. Kaplan, Silk-based biomaterials, Biomaterials 24 (2003) 401–416. [2] Z.B. Cao, X. Chen, J.R. Yao, L. Huang, Z.Z. Shao, The preparation of regenerated silk fibroin microspheres, Soft Matter 3 (2007) 910–915. [3] M.J. Chen, Z.Z. Shao, X. Chen, Paclitaxel-loaded silk fibroin nanospheres, J. Biomed. Mater. Res. A 100A (2012) 203–210.
doi:10.1016/j.jconrel.2013.08.140 Size-controllable anticancer drug loaded silk fibroin nanospheres Shuying Yua,b, Sheng Chenc,⁎, Mengjie Chena,b, Xin Chena,b,⁎ a State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China b Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China c Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China E-mail addresses: [email protected] (S. Yu), [email protected] (X. Chen).
Controlled release of ibuprofen from PCLA–PEG–PCLA based thermogels Ting Lia, Liang Chena, Tianyuan Cia, Lin Yua,b, Jiandong Dinga,b,⁎ a Key Laboratory of Molecular Engineering of Polymers of Ministry of Education, Department of Macromolecular Science, Advanced Materials Laboratory, Fudan University, Shanghai 200433, China b Key Laboratory of Smart Drug Delivery of Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai 201203, China E-mail address: [email protected] (J. Ding).