- Email: [email protected]
Novel pH- and amylase-responsive microgels for oral insulin delivery
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Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Keywords: mesoporous silica nanoparticles, pH-responsive, reduction responsive, drug delivery Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (31271028, 31570984), Innovation Program of Shanghai Municipal Education Commission (13ZZ051), International Cooperation Fund of the Science and Technology Commission of Shanghai Municipality (15540723400) and Open Foundation of State Key Laboratory for Modification of Chemical Fibers and Polymer Materials (LK1416). Reference [1] W. Feng, W. Nie, C. He, X. Zhou, L. Chen, K. Qiu, W. Wang, Z. Yin, Effect of pHresponsive alginate/chitosan multilayers coating on delivery efficiency, cellular uptake and biodistribution of mesoporous silica nanoparticles based nanocarriers, ACS Appl. Mater. Interfaces, 6 (2014) 8447-8460.
doi:10.1016/j.jconrel.2017.03.176
was loaded into both NG and NGPCaM, denoted as NG/DTX and NGPCaM/ DTX, respectively. NGPCaM/DTX exhibited enhanced cellular uptake and cytotoxicity in vitro, and improved intratumoral accumulation and antitumor efficacy in vivo in comparison to NG/DOX. The results should be attributed to the tumor targeting ability of NGPCaM/DTX by homotypic interaction compared with NG/DTX as a control (Fig. 1). In summary, the reduction-responsive NGCaM could serve as a potent excipient in tumor-homotypic targeting chemotherapy of malignancy, and the further study for NGCaM will be carried out to confirm the potential of immune activation. Keywords: prostate cancer, cell membrane, polypeptide nanogel, targetability, chemotherapy Acknowledgements This work was financially supported by National Natural Science Foundation of China (Projects 51303174, 51390484, 51233004, and 51473165). References
Tumor-homotypic reduction-responsive polypeptide nanogels for prostate cancer chemotherapy Liang Hea,b, Jixue Wanga, Hui Guoa, Chunxi Wanga,⁎, Jianxun Dingb,⁎, Xuesi Chenb a Department of Urology, The First Hospital of Jilin University, Changchun 130021, China b Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China ⁎Corresponding authors. E-mail addresses: [email protected] (C. Wang), [email protected] (J. Ding) Polymeric nanoparticles coated with membranes from various cells, such as erythrocytes, platelets, and cancer cells, exhibit fantastic potential for cancer therapy. Among them, the cancer cell membranes arouse great interests for tumor-targeting nanoparticle design recently. The tumor-derived homotypic antigens of cancer cell membranes could enhance the targetability of tumor cells-mimicking nanoparticles [1]. Herein, a reduction-responsive polypeptide nanogel (NG) of poly(L-glutamic acid)-poly(L-phenylalanine-co-L-cystine) (PLG-P(LPco-LC)) was synthesized according to the proposal of our previous work [2]. Then, the membrane of RM-1 prostate cancer (PCa) cells was extracted and coated onto the surface of smart NG, yielding NGPCaM. As depicted in Fig. 1, docetaxel (DTX), a model chemotherapeutic drug,
Fig. 1. Schematic representation of NGPCaM/DTX preparation and tumor-homotypic targeting intracellular drug delivery.
[1] R.H. Fang, C.M.J. Hu, B.T. Luk, W. Gao, J.A. Copp, Y. Tai, D.E. O'Connor, L. Zhang, Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery, Nano Lett. 14 (2014) 2181-2188. [2] L. He, D. Li, Z. Wang, W. Xu, J. Wang, H. Guo, C. Wang, J. Ding, L-Cystine-crosslinked polypeptide nanogel as a reduction-responsive excipient for prostate cancer chemotherapy, Polymers 8 (2016) 36.
doi:10.1016/j.jconrel.2017.03.177
Novel pH- and amylase-responsive microgels for oral insulin delivery Liang Liua,b, Chaoliang Hea,⁎, Ying Zhanga,b, Shun Shia,b, Zhen Zhanga,b, Xuesi Chena,⁎ a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China b University of Chinese Academy of Science, Beijing 100039, China ⁎Corresponding authors. E-mail addresses: [email protected] (L. Liu), [email protected] (C. He), [email protected] (X. Chen) A series of pH- and amylase-responsive microgels were successfully prepared via dispersion polymerization of carboxymethyl starch-graft-acrylic acid (CMS-g-AA) and 2-(isobutyl)-acrylic acid (iBAA) in absence of surfactant for oral protein delivery (Fig. 1). Transmission electron microscopic (TEM) and dynamic light scattering (DLS) revealed that the particle size ranged from 140 to 870 nm in deionized water as the CMS-g-AA content decreased from 80 to 20 wt%. The microgels shrinked markedly in artificial gastric fluid caused by H-bonding interactions and hydrophobicity to protect protein drugs from the acidic environment and emzymatic degradation, while swelled in response to neutral medium mimicking small intestine due to the ionization of carboxyl groups, leading to sitespecific protein release (Fig. 1D) [1]. Moreover, enhanced decomposition of the CMS-based microgels is expected due to the amylase in small intestine. Insulin, as a model protein, was loaded in the microgels with the drug loading content of 8.8%. The in vitro release profiles proved that insulin was released more rapidly in the presence of α-amylase within 2 hours in artificial intestinal juice (at pH 6.8). Less insulin was released in artificial gastric juice (at pH 1.2). MTT assay proved that the microgels showed no detectable cytotoxicity with relative cell viability all above 90%. The pharmacodynamic (PD) assay was performed with streptozotocin-induced diabetic rats using the microgels as a carrier for oral insulin delivery.
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
The fasting plasma glucose level was reduced continuously to 52.0% at 60 IU per kg (CMS-g-AA content: 40 wt.%) within 4 hours, which indicated the hypoglycemic effect of the microgel-based insulin oral delivery system.
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ammonium bicarbonate (NH4HCO3) as antigen release promoter, which could regulate antigen release in endosomes and lysosomes of dendritic cells (DCs). Hydrogen ions (H+) in DC endosomes and lysosomes (pH∼5.0 and 6.5) could react with NH4HCO3 to generate NH3 and CO2, which broke NPs and released antigens. After uptake by DCs, antigens encapsulated in pH-responsive PLGA NPs could escape from lysosomes into the cytoplasm and be cross-presented. Moreover, the NPs induced up-regulation of co-stimulatory molecules and stimulated cytokine production. Mouse immunization with pH-responsive PLGA NPs induced greater lymphocyte activation, more antigen-specific CD8+ T cells, stronger cytotoxic capacity (IFN-γ and granzyme B), enhanced antigen-specific IgG antibodies, and higher serum IgG2a/ IgG1, indicating cellular immunity (Fig.1). The NPs also improved generation of memory T cells to protect against reinfection. Thus, pHresponsive PLGA NPs, which induced strong cellular immune responses and offered antibody protection, could be potentially useful as effective vaccine delivery and adjuvant systems for the therapy of intracellular infectious diseases and virus infection.
Fig. 1. Synthetic route of CMS-g-AA (A) and microgel (B). TEM image of microgel (CMS-g-AA 40 wt%) in DI water (C). The scale bar represents 500 nm. Illustration of insulin-loaded microgel, which tends to swell or decomposition in response to different stimuli (D).
Keywords: carboxymethyl starch, acrylic acid, microgel, stimuli-responsive, oral insulin delivery Acknowledgements Financial support from NNSFC (21574127, 51390484 and 51321062). Reference [1] X.Y. Gao, Y. Gao, X.F. Song, Z. Zhang, C.S. Xiao, C.L. He, X.S. Chen, pH- and thermoresponsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups, J. Mater. Chem. B 41 (2013) 5578-5587.
doi:10.1016/j.jconrel.2017.03.178
Fig. 1. Production of antigen-specific antibodies in the sera of C57BL/6 mice and IL-6 release of BMDCs stimulated with NPs for 24 h. Data are expressed as means (n = 6; *p b 0.05, **p b 0.01).
Keywords: antigen intracellular rapid release, dendritic cells, pH-responsive, PLGA nanoparticles, vaccine delivery and adjuvant system Reference [1] Q. Liu, X.M. Chen, J.L. Jia, W.F. Zhang, T.Y. Yang, L.Y. Wang, G.H. Ma, pH-responsive poly(D,L-lactic-co-glycolicacid) nanoparticles with rapid antigen release behavior promote immune response, ACS Nano 9 (2015) 4925-4938.
doi:10.1016/j.jconrel.2017.03.179 Design of pH-responsive poly(D, L-lactic-co-glycolic acid) nanoparticles to promote immune response Lianyan Wang⁎, Qi Liu, Jilei Jia, Tingyuan Yang, Guanghui Ma State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China ⁎Corresponding author. E-mail address: [email protected] (L. Wang) In the quest to treat intracellular infectious diseases and virus infection, nanoparticles (NPs) have been considered to be efficient tools for inducing potent immune responses, specifically cellular immunity. Antigen processing and presenting by antigen presenting cells (APCs) could influence immune response, especially the priming of T-cellmediated cellular immunity. Here, we fabricated pH-responsive poly(D,L-lactic-co-glycolic acid) (PLGA) NPs with rapid antigen intracellular release behavior in APCs. The NPs with structure of thin shells and large inner space co-encapsulted antigen (ovalbumin, OVA) and
Polymers as tools for studying the internalization of membrane protein glutamate carboxypeptidase II Libor Kostkaa,⁎, František Sedlákb,d, Kristýna Blažkováb,c, Tomáš Etrycha, Pavel Šáchab,c, Vladimír Šubra, Jan Konvalinkab,c a Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, 162 06 Prague, Czech Republic b Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Fleming sq 2., 166 10, Prague, 6,Czech Republic c Faculty of Science, Charles University, Hlavova 8, 12843 Prague 2, Czech Republic d First Faculty of Medicine, Charles University, Kateřinská 32, 12108 Prague 2, Czech Republic ⁎Corresponding author. E-mail address: [email protected] (L. Kostka)
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Keywords: mesoporous silica nanoparticles, pH-responsive, reduction responsive, drug delivery Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (31271028, 31570984), Innovation Program of Shanghai Municipal Education Commission (13ZZ051), International Cooperation Fund of the Science and Technology Commission of Shanghai Municipality (15540723400) and Open Foundation of State Key Laboratory for Modification of Chemical Fibers and Polymer Materials (LK1416). Reference [1] W. Feng, W. Nie, C. He, X. Zhou, L. Chen, K. Qiu, W. Wang, Z. Yin, Effect of pHresponsive alginate/chitosan multilayers coating on delivery efficiency, cellular uptake and biodistribution of mesoporous silica nanoparticles based nanocarriers, ACS Appl. Mater. Interfaces, 6 (2014) 8447-8460.
doi:10.1016/j.jconrel.2017.03.176
was loaded into both NG and NGPCaM, denoted as NG/DTX and NGPCaM/ DTX, respectively. NGPCaM/DTX exhibited enhanced cellular uptake and cytotoxicity in vitro, and improved intratumoral accumulation and antitumor efficacy in vivo in comparison to NG/DOX. The results should be attributed to the tumor targeting ability of NGPCaM/DTX by homotypic interaction compared with NG/DTX as a control (Fig. 1). In summary, the reduction-responsive NGCaM could serve as a potent excipient in tumor-homotypic targeting chemotherapy of malignancy, and the further study for NGCaM will be carried out to confirm the potential of immune activation. Keywords: prostate cancer, cell membrane, polypeptide nanogel, targetability, chemotherapy Acknowledgements This work was financially supported by National Natural Science Foundation of China (Projects 51303174, 51390484, 51233004, and 51473165). References
Tumor-homotypic reduction-responsive polypeptide nanogels for prostate cancer chemotherapy Liang Hea,b, Jixue Wanga, Hui Guoa, Chunxi Wanga,⁎, Jianxun Dingb,⁎, Xuesi Chenb a Department of Urology, The First Hospital of Jilin University, Changchun 130021, China b Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China ⁎Corresponding authors. E-mail addresses: [email protected] (C. Wang), [email protected] (J. Ding) Polymeric nanoparticles coated with membranes from various cells, such as erythrocytes, platelets, and cancer cells, exhibit fantastic potential for cancer therapy. Among them, the cancer cell membranes arouse great interests for tumor-targeting nanoparticle design recently. The tumor-derived homotypic antigens of cancer cell membranes could enhance the targetability of tumor cells-mimicking nanoparticles [1]. Herein, a reduction-responsive polypeptide nanogel (NG) of poly(L-glutamic acid)-poly(L-phenylalanine-co-L-cystine) (PLG-P(LPco-LC)) was synthesized according to the proposal of our previous work [2]. Then, the membrane of RM-1 prostate cancer (PCa) cells was extracted and coated onto the surface of smart NG, yielding NGPCaM. As depicted in Fig. 1, docetaxel (DTX), a model chemotherapeutic drug,
Fig. 1. Schematic representation of NGPCaM/DTX preparation and tumor-homotypic targeting intracellular drug delivery.
[1] R.H. Fang, C.M.J. Hu, B.T. Luk, W. Gao, J.A. Copp, Y. Tai, D.E. O'Connor, L. Zhang, Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery, Nano Lett. 14 (2014) 2181-2188. [2] L. He, D. Li, Z. Wang, W. Xu, J. Wang, H. Guo, C. Wang, J. Ding, L-Cystine-crosslinked polypeptide nanogel as a reduction-responsive excipient for prostate cancer chemotherapy, Polymers 8 (2016) 36.
doi:10.1016/j.jconrel.2017.03.177
Novel pH- and amylase-responsive microgels for oral insulin delivery Liang Liua,b, Chaoliang Hea,⁎, Ying Zhanga,b, Shun Shia,b, Zhen Zhanga,b, Xuesi Chena,⁎ a Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China b University of Chinese Academy of Science, Beijing 100039, China ⁎Corresponding authors. E-mail addresses: [email protected] (L. Liu), [email protected] (C. He), [email protected] (X. Chen) A series of pH- and amylase-responsive microgels were successfully prepared via dispersion polymerization of carboxymethyl starch-graft-acrylic acid (CMS-g-AA) and 2-(isobutyl)-acrylic acid (iBAA) in absence of surfactant for oral protein delivery (Fig. 1). Transmission electron microscopic (TEM) and dynamic light scattering (DLS) revealed that the particle size ranged from 140 to 870 nm in deionized water as the CMS-g-AA content decreased from 80 to 20 wt%. The microgels shrinked markedly in artificial gastric fluid caused by H-bonding interactions and hydrophobicity to protect protein drugs from the acidic environment and emzymatic degradation, while swelled in response to neutral medium mimicking small intestine due to the ionization of carboxyl groups, leading to sitespecific protein release (Fig. 1D) [1]. Moreover, enhanced decomposition of the CMS-based microgels is expected due to the amylase in small intestine. Insulin, as a model protein, was loaded in the microgels with the drug loading content of 8.8%. The in vitro release profiles proved that insulin was released more rapidly in the presence of α-amylase within 2 hours in artificial intestinal juice (at pH 6.8). Less insulin was released in artificial gastric juice (at pH 1.2). MTT assay proved that the microgels showed no detectable cytotoxicity with relative cell viability all above 90%. The pharmacodynamic (PD) assay was performed with streptozotocin-induced diabetic rats using the microgels as a carrier for oral insulin delivery.
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
The fasting plasma glucose level was reduced continuously to 52.0% at 60 IU per kg (CMS-g-AA content: 40 wt.%) within 4 hours, which indicated the hypoglycemic effect of the microgel-based insulin oral delivery system.
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ammonium bicarbonate (NH4HCO3) as antigen release promoter, which could regulate antigen release in endosomes and lysosomes of dendritic cells (DCs). Hydrogen ions (H+) in DC endosomes and lysosomes (pH∼5.0 and 6.5) could react with NH4HCO3 to generate NH3 and CO2, which broke NPs and released antigens. After uptake by DCs, antigens encapsulated in pH-responsive PLGA NPs could escape from lysosomes into the cytoplasm and be cross-presented. Moreover, the NPs induced up-regulation of co-stimulatory molecules and stimulated cytokine production. Mouse immunization with pH-responsive PLGA NPs induced greater lymphocyte activation, more antigen-specific CD8+ T cells, stronger cytotoxic capacity (IFN-γ and granzyme B), enhanced antigen-specific IgG antibodies, and higher serum IgG2a/ IgG1, indicating cellular immunity (Fig.1). The NPs also improved generation of memory T cells to protect against reinfection. Thus, pHresponsive PLGA NPs, which induced strong cellular immune responses and offered antibody protection, could be potentially useful as effective vaccine delivery and adjuvant systems for the therapy of intracellular infectious diseases and virus infection.
Fig. 1. Synthetic route of CMS-g-AA (A) and microgel (B). TEM image of microgel (CMS-g-AA 40 wt%) in DI water (C). The scale bar represents 500 nm. Illustration of insulin-loaded microgel, which tends to swell or decomposition in response to different stimuli (D).
Keywords: carboxymethyl starch, acrylic acid, microgel, stimuli-responsive, oral insulin delivery Acknowledgements Financial support from NNSFC (21574127, 51390484 and 51321062). Reference [1] X.Y. Gao, Y. Gao, X.F. Song, Z. Zhang, C.S. Xiao, C.L. He, X.S. Chen, pH- and thermoresponsive poly(N-isopropylacrylamide-co-acrylic acid derivative) copolymers and hydrogels with LCST dependent on pH and alkyl side groups, J. Mater. Chem. B 41 (2013) 5578-5587.
doi:10.1016/j.jconrel.2017.03.178
Fig. 1. Production of antigen-specific antibodies in the sera of C57BL/6 mice and IL-6 release of BMDCs stimulated with NPs for 24 h. Data are expressed as means (n = 6; *p b 0.05, **p b 0.01).
Keywords: antigen intracellular rapid release, dendritic cells, pH-responsive, PLGA nanoparticles, vaccine delivery and adjuvant system Reference [1] Q. Liu, X.M. Chen, J.L. Jia, W.F. Zhang, T.Y. Yang, L.Y. Wang, G.H. Ma, pH-responsive poly(D,L-lactic-co-glycolicacid) nanoparticles with rapid antigen release behavior promote immune response, ACS Nano 9 (2015) 4925-4938.
doi:10.1016/j.jconrel.2017.03.179 Design of pH-responsive poly(D, L-lactic-co-glycolic acid) nanoparticles to promote immune response Lianyan Wang⁎, Qi Liu, Jilei Jia, Tingyuan Yang, Guanghui Ma State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China ⁎Corresponding author. E-mail address: [email protected] (L. Wang) In the quest to treat intracellular infectious diseases and virus infection, nanoparticles (NPs) have been considered to be efficient tools for inducing potent immune responses, specifically cellular immunity. Antigen processing and presenting by antigen presenting cells (APCs) could influence immune response, especially the priming of T-cellmediated cellular immunity. Here, we fabricated pH-responsive poly(D,L-lactic-co-glycolic acid) (PLGA) NPs with rapid antigen intracellular release behavior in APCs. The NPs with structure of thin shells and large inner space co-encapsulted antigen (ovalbumin, OVA) and
Polymers as tools for studying the internalization of membrane protein glutamate carboxypeptidase II Libor Kostkaa,⁎, František Sedlákb,d, Kristýna Blažkováb,c, Tomáš Etrycha, Pavel Šáchab,c, Vladimír Šubra, Jan Konvalinkab,c a Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovsky sq. 2, 162 06 Prague, Czech Republic b Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Fleming sq 2., 166 10, Prague, 6,Czech Republic c Faculty of Science, Charles University, Hlavova 8, 12843 Prague 2, Czech Republic d First Faculty of Medicine, Charles University, Kateřinská 32, 12108 Prague 2, Czech Republic ⁎Corresponding author. E-mail address: [email protected] (L. Kostka)