- Email: [email protected]
Multifunctional polyethylenimine-based nanoplatform for targeted anti-cancer drug delivery to tumors in vivo
e10
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Structural and dynamic properties of different DPPC lipid membranes using a coarse-grained model Bei Lia,⁎, Yuan Chengb, Jingjie Yeob, Narayanaswamy Sridharb, Yongwei Zhangb a School of Materials Science and Engineering, Wuhan University of Technology, Materials Building, West Campus, Wuhan 430070, China b Institute of High Performance Computing, 1 Fusionopolis Way, #16-16 Connexis North, Singapore 138632, Singapore ⁎Corresponding author. E-mail address: [email protected] (B. Li) Lipid membranes play significant roles in cells as semi-permeable “control gates” for maintaining concentrations and separating the internal compartments from the outer environment [1]. In this work, coarse-grained molecular dynamics simulations of different DPPC lipid bilayer systems were performed using the Martini force field at a semi-isotropic pressure of 1 bar and 323 K. The systems consisted of a number of DPPC molecules varying from NDPPC = 128 to NDPPC = 2048, and about 30 water molecules per lipid to give a full level of hydration [2]. The equilibration of the systems was monitored by examining the time evolution of the temperature and energy of the DPPC systems. After achieving the equilibration, the structural properties of the systems were demonstrated by examining the volume and area per lipid, the electron density profile, the P2 order parameter, and the lipid bilayer thickness (Fig. 1). It was shown from the volume/area per lipid and the electron density profiles that the DPPC system had a more stable configuration with a larger number of DPPC molecules. Though, the system size had a negligible effect on the order parameter calculation, a best agreement with the atomic simulation in the lipid bilayer thickness was found for the system with NDPPC = 2048. On the other hand, the lipid dynamics was quantified by computing the lateral diffusion coefficients of the lipid molecules. It was shown that the diffusion coefficients of DPPC chains lied in a range of 19 μm2/s to 23 μm2/s for the four different DPPC systems, indicating that the system size has a weak effect on the diffusion dynamics of the DPPC lipid bilayers.
Fig. 1. The electron density profiles for DPPC lipid bilayer systems with different number of DPPC chains NDPPC. The bilayer center is located at around 0.2 nm.
Keywords: molecular dynamics, coarse-grained model, DPPC lipid bilayer
References [1] M.G. van, D.R. Voelker, G.W. Feigenson, Membrane lipids: where they are and how they behave, Nat. Rev. Mol. Cell Biol. 9 (2008) 112-124. [2] C.H. Huang, J.R. Lapides, I.W. Levin, Phase-transition behavior of saturated, symmetric chain phospholipid bilayer dispersions determined by Raman spectroscopy: correlation between spectral and thermodynamic parameters, J. Am. Chem. Soc. 104 (1982) 5926-5930.
doi:10.1016/j.jconrel.2017.03.051
Multifunctional polyethylenimine-based nanoplatform for targeted anti-cancer drug delivery to tumors in vivo Benqing Zhoua, Lingzhou Zhaob, Jinhua Zhaob, Xiangyang Shia,⁎ State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China b Department of Nuclear Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China ⁎Corresponding author. E-mail address: [email protected] (X. Shi) a
Hyperbranched polyethylenimine (PEI) possessing good water solubility has been selected as an effective vehicle to encapsulate nanoparticles or drugs for different biomedical applications [1-3]. Here, we report the synthesis and characterization of multifunctional PEI as an effective vehicle to encapsulate an anticancer drug doxorubicin (DOX) for targeted cancer therapy in vivo. In this study, PEI was sequentially modified with polyethylene glycol (PEG) monomethyl ether, folic acid (FA)-linked PEG, and fluorescein isothiocyanate (FI), followed by acetylation of the remaining PEI surface amines. The formed FA-targeted multifunctional PEI (FA-mPEI) was used as a vehicle to encapsulate DOX. We show that the formed FA-mPEI/DOX complexes with each PEI encapsulating 6.9 DOX molecules are water dispersible, and can release DOX in a sustained manner with a higher release rate at an acidic pH condition. Furthermore, the complexes displayed specific therapeutic efficacy to cancer cells in vitro and antitumor activity in vivo (Fig. 1). Simultaneously in vivo toxicity evaluation revealed that the complexes displayed good organ compatibility. The designed multifunctional PEI may hold great promise to be used as an effective vehicle for targeted cancer chemotherapy applications.
Fig. 1. (a) Schematic illustration of the FA-mPEI/DOX complexes; (b) the photo of HeLa cells treated with FA-mPEI/DOX complexes at DOX concentrations of 5 g/mL for 24 h (the white circle refers to the complexes); (c) the relative tumor volume as a function of time post treatment under different conditions. Significance level were indicated with *p b 0.05, and **p b 0.01, respectively.
Keywords: polyethylenimine, PEG, folic acid, doxorubicin, drug delivery
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Acknowledgement This research is supported by the National Natural Science Foundation of China (221273032) and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning. References [1] S. Hoebel, A. Loos, D. Appelhans, S. Schwarz, J. Seidel, B. Voit, A. Aigner, Maltoseand maltotriose-modified, hyperbranched poly(ethylene imine)s (OM-PEIs): physicochemical and biological properties of DNA and siRNA complexes. J. Control. Release 149 (2011) 146-158. [2] B. Zhou, J. Yang, C. Peng, J. Zhu, Y. Tang, X. Zhu, M. Shen, G. Zhang, X. Shi, PEGylated polyethylenimine-entrapped gold nanoparticles modified with folic acid for targeted tumor CT imaging. Colloids Surf., B 140 (2016) 489-496. [3] B. Zhou, L. Zheng, C. Peng, D. Li, J. Li, S. Wen, M. Shen, G. Zhang, X. Shi, Synthesis and characterization of PEGylated polyethylenimine-entrapped gold nanoparticles for blood pool and tumor CT imaging. ACS Appl. Mater. Interfaces 6 (2014) 17190-17199.
e11
about 8 ~ 22 μm, and large numbers of pores on the surface and the inner (Fig. 1). Due to the numerous carboxyl groups, the DOX loading capacity and loading efficiency of the magnetic microspheres reached 56.2% and 93.7%, respectively. The in vitro drug release behavior of the DOX-loaded magnetic microspheres showed that the cumulative drug release was 24.5% and 40.6% within 24 h at pH 7.4 and pH 5.0, respectively. This phenomenon was ascribed to the following factors. Firstly, the electrostatic interaction between the carboxyl groups of PAA segments and the amino group of DOX was weakened in the acidic media, which was in favor of the release of DOX. In addition, DOX had a higher solubility in acidic media [2]. Keywords: pH-responsive, magnetic, porous, Pickering HIPEs, controlled release References
doi:10.1016/j.jconrel.2017.03.052
[1] R. Cheng, F.H. Meng, C. Deng, H.-A. Klok, Z.Y. Zhong, Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery, Biomaterials 34 (2013) 3647-3657. [2] L. Du, Y. Jin, W. Zhou, J. Zhao, Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin-loaded poly (D,L-lactide-co-glycolide)-methoxy-poly (ethylene glycol) nanodroplets, Ultrasound Med. Biol. 37 (2011) 1252-1258.
pH stimuli-responsive magnetic porous poly(acrylic acid) microspheres prepared via Pickering HIPEs templating for targeted and controlled release of doxorubicin
doi:10.1016/j.jconrel.2017.03.053
Xinyue Liua, Qian Liua, Linjing Lia, Bin Mub,⁎ The Second Hospital of Lanzhou University, Lanzhou 730000, China b Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China ⁎Corresponding author.
a
In order to weaken the toxic side effects of the antitumor drugs in normal tissues to the utmost extent, various pH stimuli-responsive drug delivery systems, especially polymer-based carriers have been designed for the targeted and controlled release of the antitumor drugs due to the pH difference between of the normal and tumor tissues [1]. Here, pH stimuli-responsive magnetic porous poly(acrylic acid) microspheres were prepared using magnetic particles stabilized Pickering high internal phase emulsions (HIPEs) templating. The microspheres following the coating with Ca2 + crosslinked sodium alginate could serve as carrier for targeted and controlled release of doxorubicin (DOX). The as-prepared microspheres had a diameter of
Fig. 1. SEM image of the magnetic porous poly(acrylic acid) microsphere prepared using magnetic particles stabilized Pickering HIPEs templating.
Novel insights into the raw material variability and its impact on drug release from high dose controlled release tablet Yi Zhang, Bing Xu⁎, Fei Sun, Shengyun Dai, Xinyuan Shi, Yanjiang Qiao⁎ Research Center of TCM Information Engineering, Beijing University of Chinese Medicine, Beijing 100029, China ⁎Corresponding authors. E-mail addresses: [email protected] (B. Xu), [email protected] (Y. Qiao) The controlled release matrix tablet of Panax Notoginseng Saponins (PNS) has many advantages over the clinically used immediate release tablet of PNS. Generally, active ingredients in PNS extract powders are specified in the Chinese Pharmacopeia (2015 Edition, Volume I). However, the physical properties of PNS raw materials are at high risk of suffering from lot-to-lot and sourceto-source variability due to different preparation processes. The aim of this study was to identify the critical materials attributes that influence the in vitro dissolution of PNS matrix tablet. 12 batches of PNS powders from different vendors were collected, and the tablet formulations consisting of PNS (57.0%), hydroxypropyl methylcellulose K4M (21.0%) and other excipients were prepared by direct compression. The SeDeM expert system [1] was introduced to characterize the PNS powders, whose physical diversities were shown in Fig. 1a. Three main components in PNS from the same batch, i.e. Notoginsenoside R1, Ginsenoside Rg1 and Ginsenoside Rb1 were released synchronously in the 0-12 h period. However, the release behaviors of those components from different batches exhibited considerable variations with f2 values ranging from 49 to 91 (Fig. 1b). Kinetic analysis using Korsmeyer-Peppas model confirmed the erosion mechanism. Chemometric evaluation by partial least squares suggested that the dissolution of active ingredients was positively correlated with the hygroscopicity and the particle size of PNS, and was negatively correlated with the loss on drying. Further work should be conducted to develop a control strategy in line with quality by design principles to assure the product quality consistence.
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Structural and dynamic properties of different DPPC lipid membranes using a coarse-grained model Bei Lia,⁎, Yuan Chengb, Jingjie Yeob, Narayanaswamy Sridharb, Yongwei Zhangb a School of Materials Science and Engineering, Wuhan University of Technology, Materials Building, West Campus, Wuhan 430070, China b Institute of High Performance Computing, 1 Fusionopolis Way, #16-16 Connexis North, Singapore 138632, Singapore ⁎Corresponding author. E-mail address: [email protected] (B. Li) Lipid membranes play significant roles in cells as semi-permeable “control gates” for maintaining concentrations and separating the internal compartments from the outer environment [1]. In this work, coarse-grained molecular dynamics simulations of different DPPC lipid bilayer systems were performed using the Martini force field at a semi-isotropic pressure of 1 bar and 323 K. The systems consisted of a number of DPPC molecules varying from NDPPC = 128 to NDPPC = 2048, and about 30 water molecules per lipid to give a full level of hydration [2]. The equilibration of the systems was monitored by examining the time evolution of the temperature and energy of the DPPC systems. After achieving the equilibration, the structural properties of the systems were demonstrated by examining the volume and area per lipid, the electron density profile, the P2 order parameter, and the lipid bilayer thickness (Fig. 1). It was shown from the volume/area per lipid and the electron density profiles that the DPPC system had a more stable configuration with a larger number of DPPC molecules. Though, the system size had a negligible effect on the order parameter calculation, a best agreement with the atomic simulation in the lipid bilayer thickness was found for the system with NDPPC = 2048. On the other hand, the lipid dynamics was quantified by computing the lateral diffusion coefficients of the lipid molecules. It was shown that the diffusion coefficients of DPPC chains lied in a range of 19 μm2/s to 23 μm2/s for the four different DPPC systems, indicating that the system size has a weak effect on the diffusion dynamics of the DPPC lipid bilayers.
Fig. 1. The electron density profiles for DPPC lipid bilayer systems with different number of DPPC chains NDPPC. The bilayer center is located at around 0.2 nm.
Keywords: molecular dynamics, coarse-grained model, DPPC lipid bilayer
References [1] M.G. van, D.R. Voelker, G.W. Feigenson, Membrane lipids: where they are and how they behave, Nat. Rev. Mol. Cell Biol. 9 (2008) 112-124. [2] C.H. Huang, J.R. Lapides, I.W. Levin, Phase-transition behavior of saturated, symmetric chain phospholipid bilayer dispersions determined by Raman spectroscopy: correlation between spectral and thermodynamic parameters, J. Am. Chem. Soc. 104 (1982) 5926-5930.
doi:10.1016/j.jconrel.2017.03.051
Multifunctional polyethylenimine-based nanoplatform for targeted anti-cancer drug delivery to tumors in vivo Benqing Zhoua, Lingzhou Zhaob, Jinhua Zhaob, Xiangyang Shia,⁎ State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China b Department of Nuclear Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China ⁎Corresponding author. E-mail address: [email protected] (X. Shi) a
Hyperbranched polyethylenimine (PEI) possessing good water solubility has been selected as an effective vehicle to encapsulate nanoparticles or drugs for different biomedical applications [1-3]. Here, we report the synthesis and characterization of multifunctional PEI as an effective vehicle to encapsulate an anticancer drug doxorubicin (DOX) for targeted cancer therapy in vivo. In this study, PEI was sequentially modified with polyethylene glycol (PEG) monomethyl ether, folic acid (FA)-linked PEG, and fluorescein isothiocyanate (FI), followed by acetylation of the remaining PEI surface amines. The formed FA-targeted multifunctional PEI (FA-mPEI) was used as a vehicle to encapsulate DOX. We show that the formed FA-mPEI/DOX complexes with each PEI encapsulating 6.9 DOX molecules are water dispersible, and can release DOX in a sustained manner with a higher release rate at an acidic pH condition. Furthermore, the complexes displayed specific therapeutic efficacy to cancer cells in vitro and antitumor activity in vivo (Fig. 1). Simultaneously in vivo toxicity evaluation revealed that the complexes displayed good organ compatibility. The designed multifunctional PEI may hold great promise to be used as an effective vehicle for targeted cancer chemotherapy applications.
Fig. 1. (a) Schematic illustration of the FA-mPEI/DOX complexes; (b) the photo of HeLa cells treated with FA-mPEI/DOX complexes at DOX concentrations of 5 g/mL for 24 h (the white circle refers to the complexes); (c) the relative tumor volume as a function of time post treatment under different conditions. Significance level were indicated with *p b 0.05, and **p b 0.01, respectively.
Keywords: polyethylenimine, PEG, folic acid, doxorubicin, drug delivery
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Acknowledgement This research is supported by the National Natural Science Foundation of China (221273032) and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning. References [1] S. Hoebel, A. Loos, D. Appelhans, S. Schwarz, J. Seidel, B. Voit, A. Aigner, Maltoseand maltotriose-modified, hyperbranched poly(ethylene imine)s (OM-PEIs): physicochemical and biological properties of DNA and siRNA complexes. J. Control. Release 149 (2011) 146-158. [2] B. Zhou, J. Yang, C. Peng, J. Zhu, Y. Tang, X. Zhu, M. Shen, G. Zhang, X. Shi, PEGylated polyethylenimine-entrapped gold nanoparticles modified with folic acid for targeted tumor CT imaging. Colloids Surf., B 140 (2016) 489-496. [3] B. Zhou, L. Zheng, C. Peng, D. Li, J. Li, S. Wen, M. Shen, G. Zhang, X. Shi, Synthesis and characterization of PEGylated polyethylenimine-entrapped gold nanoparticles for blood pool and tumor CT imaging. ACS Appl. Mater. Interfaces 6 (2014) 17190-17199.
e11
about 8 ~ 22 μm, and large numbers of pores on the surface and the inner (Fig. 1). Due to the numerous carboxyl groups, the DOX loading capacity and loading efficiency of the magnetic microspheres reached 56.2% and 93.7%, respectively. The in vitro drug release behavior of the DOX-loaded magnetic microspheres showed that the cumulative drug release was 24.5% and 40.6% within 24 h at pH 7.4 and pH 5.0, respectively. This phenomenon was ascribed to the following factors. Firstly, the electrostatic interaction between the carboxyl groups of PAA segments and the amino group of DOX was weakened in the acidic media, which was in favor of the release of DOX. In addition, DOX had a higher solubility in acidic media [2]. Keywords: pH-responsive, magnetic, porous, Pickering HIPEs, controlled release References
doi:10.1016/j.jconrel.2017.03.052
[1] R. Cheng, F.H. Meng, C. Deng, H.-A. Klok, Z.Y. Zhong, Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery, Biomaterials 34 (2013) 3647-3657. [2] L. Du, Y. Jin, W. Zhou, J. Zhao, Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin-loaded poly (D,L-lactide-co-glycolide)-methoxy-poly (ethylene glycol) nanodroplets, Ultrasound Med. Biol. 37 (2011) 1252-1258.
pH stimuli-responsive magnetic porous poly(acrylic acid) microspheres prepared via Pickering HIPEs templating for targeted and controlled release of doxorubicin
doi:10.1016/j.jconrel.2017.03.053
Xinyue Liua, Qian Liua, Linjing Lia, Bin Mub,⁎ The Second Hospital of Lanzhou University, Lanzhou 730000, China b Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China ⁎Corresponding author.
a
In order to weaken the toxic side effects of the antitumor drugs in normal tissues to the utmost extent, various pH stimuli-responsive drug delivery systems, especially polymer-based carriers have been designed for the targeted and controlled release of the antitumor drugs due to the pH difference between of the normal and tumor tissues [1]. Here, pH stimuli-responsive magnetic porous poly(acrylic acid) microspheres were prepared using magnetic particles stabilized Pickering high internal phase emulsions (HIPEs) templating. The microspheres following the coating with Ca2 + crosslinked sodium alginate could serve as carrier for targeted and controlled release of doxorubicin (DOX). The as-prepared microspheres had a diameter of
Fig. 1. SEM image of the magnetic porous poly(acrylic acid) microsphere prepared using magnetic particles stabilized Pickering HIPEs templating.
Novel insights into the raw material variability and its impact on drug release from high dose controlled release tablet Yi Zhang, Bing Xu⁎, Fei Sun, Shengyun Dai, Xinyuan Shi, Yanjiang Qiao⁎ Research Center of TCM Information Engineering, Beijing University of Chinese Medicine, Beijing 100029, China ⁎Corresponding authors. E-mail addresses: [email protected] (B. Xu), [email protected] (Y. Qiao) The controlled release matrix tablet of Panax Notoginseng Saponins (PNS) has many advantages over the clinically used immediate release tablet of PNS. Generally, active ingredients in PNS extract powders are specified in the Chinese Pharmacopeia (2015 Edition, Volume I). However, the physical properties of PNS raw materials are at high risk of suffering from lot-to-lot and sourceto-source variability due to different preparation processes. The aim of this study was to identify the critical materials attributes that influence the in vitro dissolution of PNS matrix tablet. 12 batches of PNS powders from different vendors were collected, and the tablet formulations consisting of PNS (57.0%), hydroxypropyl methylcellulose K4M (21.0%) and other excipients were prepared by direct compression. The SeDeM expert system [1] was introduced to characterize the PNS powders, whose physical diversities were shown in Fig. 1a. Three main components in PNS from the same batch, i.e. Notoginsenoside R1, Ginsenoside Rg1 and Ginsenoside Rb1 were released synchronously in the 0-12 h period. However, the release behaviors of those components from different batches exhibited considerable variations with f2 values ranging from 49 to 91 (Fig. 1b). Kinetic analysis using Korsmeyer-Peppas model confirmed the erosion mechanism. Chemometric evaluation by partial least squares suggested that the dissolution of active ingredients was positively correlated with the hygroscopicity and the particle size of PNS, and was negatively correlated with the loss on drying. Further work should be conducted to develop a control strategy in line with quality by design principles to assure the product quality consistence.