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Acid-liable prodrug for doxorubicin release
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ChinaNanomedicine Abstracts / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 449–575
Remotely controlled red blood cell carriers for cancer targeting and nearinfrared light-triggered drug release in combined photothermal chemotherapy Xiaoqi Sun, Chao Wang, Min Gao, Aiyan Hu, Zhuang Liu⁎, Institute of Functional Nano & Soft Materials (FUNSOM) Soochow University, Suzhou, Jiangsu, China ⁎Corresponding author. E-mail address: [email protected] (Z. Liu) Red blood cells (RBCs), the “innate carriers” in our blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, we develop a tumor angiogenesis targeting, light stimulus–response RBC-based DDS by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, whose surface is modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of RBCs would be destructed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release are demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal-chemotherapy. Our work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.
http://dx.doi.org/10.1016/j.nano.2015.12.283
RGD targeting, pH-sensitive hybrid micelles to overcome drug resistance in cancer cells Yuling Bao, Xiaomeng Hu, Qingle Song, Dong Wang, Yu Sun, Zhiping Zhang⁎, Tongji School of Pharmacy& National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, China ⁎Corresponding author. E-mail address: [email protected] (Z. Zhang) A novel schiff-base conjugated prodrug based on vitamin E TPGS and doxorubicin (TPGS-schiff-DOX) was synthesized for overcoming drug resistance in cancer cells.1 It can be quickly cleaved after endocytosis by cancer cells to cause release of the active drug and consequent cancer cell cytotoxicity. The released TPGS can bind with P-gp and thus restrain its activity and reduce the efflux of DOX. The hybrid micelles (~140 nm) were obtained by mixing the prodrug with DSPE-PEG2000/DSPE-PEG2000-MAL at a ratio of 3:1 followed by cRGD conjugation. At the acidic pH of 5.0, simulating the lysosomal acidic environment, around 60% of DOX was released after 24 h incubation, which was almost 4-fold than that at neutral pH. The hybrid micelles exhibited higher cytotoxicity than free DOX against DOX-resistant MCF-7/ADR cells. Pharmacokinetic investigation showed 5- and 7.7-fold increases in the half-life and area-under-the-curve (AUC) of DOX, respectively for the hybrid micelles compared with free DOX after intravenous administration. Superior antitumor activity was also demonstrated in H22 tumor model with reduced side effect in heart. All these results implied that This research is supported by the National Basic Research Program of China (2012CB932501), Nature Science Fund of China (21204024 and 81373360), and Innovative Research Fund.
the cRGD targeting, pH-sensitive hybrid micelles have significant potential for overcoming DOX resistance in cancer cells.
Figure 1. (A) Self-assembly of hybrid micelles. (B) In vitro and (C) in vivo antitumor activities.
http://dx.doi.org/10.1016/j.nano.2015.12.284
Acid-liable prodrug for doxorubicin release Lingli Dong, Xintao Zheng, Rong Jin⁎, Aoneng Cao⁎, Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai, P.R. China ⁎Corresponding authors. E-mail addresses: [email protected] (R. Jin), [email protected] (A. Cao) Polymer-based nanomicelles and polymersomes have been widely investigated as nano-carriers for controlled drug release. However, they are often associated with a low drug-loading efficiency, relatively poor structural stability under physiological conditions and undesirable premature drug release. By contrast, drug-conjugated polymers, also referred to as prodrugs, do not have these issues as a result of covalent linking of drug to polymers. In this study, we reported on acid-liable dextran-doxorubicin (Dex-DOX) prodrug for controlled DOX release. Dextranhydrazine (Mw = 10 k Da) was prepared by reacting dextran p-nitrophenyl carbonate with tert-butoxycarbonylhydrazine (BocNHNH2), following with the removal of Boc-protective group. Anticancer drug DOX was then conjugated to the dextran via the formation of acid-labile hydrazone bond (Figure 1, A), which is stable at physiological pH but cleavable at endosomal pH. Unreacted or encapsulated DOX was removed by complete dialysis in DMSO and then in water. DOX loading capacity of Dex-DOX, defined as weight percentage of DOX in the prodrug, was determined to be 18.4 wt%. To confirm acid-sensitive DOX release from Dex-DOX, DOX release rate was measured at pH 5.5 and 7.4, respectively (Figure 1, B). As expected, Dex-DOX prodrug exhibited pHdependent DOX release profile. At pH 5.5, about 67% of DOX was released from the prodrug after 36 h. However, at pH 7.4, only 39% of DOX was liberated at the same time. This accelerated DOX release under acidic condition is ascribed to the degradation of acid-liable hydrazone bond. This result thus indicates the potential of Dex-DOX as an acid-sensitive prodrug for anti-cancer therapy.
Figure 1. (A) Chemical structure of Dex-DOX prodrug. (B) pH-dependent DOX release profile of Dex-DOX at pH 5.5 and 7.4.
This work was supported by the National Basic Research Program of China (973 Program No. 2011CB933402) and the China Natural Science Foundation (No. 21371117).
http://dx.doi.org/10.1016/j.nano.2015.12.285
ChinaNanomedicine Abstracts / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 449–575
Remotely controlled red blood cell carriers for cancer targeting and nearinfrared light-triggered drug release in combined photothermal chemotherapy Xiaoqi Sun, Chao Wang, Min Gao, Aiyan Hu, Zhuang Liu⁎, Institute of Functional Nano & Soft Materials (FUNSOM) Soochow University, Suzhou, Jiangsu, China ⁎Corresponding author. E-mail address: [email protected] (Z. Liu) Red blood cells (RBCs), the “innate carriers” in our blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, we develop a tumor angiogenesis targeting, light stimulus–response RBC-based DDS by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, whose surface is modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of RBCs would be destructed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release are demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal-chemotherapy. Our work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.
http://dx.doi.org/10.1016/j.nano.2015.12.283
RGD targeting, pH-sensitive hybrid micelles to overcome drug resistance in cancer cells Yuling Bao, Xiaomeng Hu, Qingle Song, Dong Wang, Yu Sun, Zhiping Zhang⁎, Tongji School of Pharmacy& National Engineering Research Center for Nanomedicine, Huazhong University of Science & Technology, Wuhan, China ⁎Corresponding author. E-mail address: [email protected] (Z. Zhang) A novel schiff-base conjugated prodrug based on vitamin E TPGS and doxorubicin (TPGS-schiff-DOX) was synthesized for overcoming drug resistance in cancer cells.1 It can be quickly cleaved after endocytosis by cancer cells to cause release of the active drug and consequent cancer cell cytotoxicity. The released TPGS can bind with P-gp and thus restrain its activity and reduce the efflux of DOX. The hybrid micelles (~140 nm) were obtained by mixing the prodrug with DSPE-PEG2000/DSPE-PEG2000-MAL at a ratio of 3:1 followed by cRGD conjugation. At the acidic pH of 5.0, simulating the lysosomal acidic environment, around 60% of DOX was released after 24 h incubation, which was almost 4-fold than that at neutral pH. The hybrid micelles exhibited higher cytotoxicity than free DOX against DOX-resistant MCF-7/ADR cells. Pharmacokinetic investigation showed 5- and 7.7-fold increases in the half-life and area-under-the-curve (AUC) of DOX, respectively for the hybrid micelles compared with free DOX after intravenous administration. Superior antitumor activity was also demonstrated in H22 tumor model with reduced side effect in heart. All these results implied that This research is supported by the National Basic Research Program of China (2012CB932501), Nature Science Fund of China (21204024 and 81373360), and Innovative Research Fund.
the cRGD targeting, pH-sensitive hybrid micelles have significant potential for overcoming DOX resistance in cancer cells.
Figure 1. (A) Self-assembly of hybrid micelles. (B) In vitro and (C) in vivo antitumor activities.
http://dx.doi.org/10.1016/j.nano.2015.12.284
Acid-liable prodrug for doxorubicin release Lingli Dong, Xintao Zheng, Rong Jin⁎, Aoneng Cao⁎, Institute of Nanochemistry and Nanobiology, Shanghai University, Shanghai, P.R. China ⁎Corresponding authors. E-mail addresses: [email protected] (R. Jin), [email protected] (A. Cao) Polymer-based nanomicelles and polymersomes have been widely investigated as nano-carriers for controlled drug release. However, they are often associated with a low drug-loading efficiency, relatively poor structural stability under physiological conditions and undesirable premature drug release. By contrast, drug-conjugated polymers, also referred to as prodrugs, do not have these issues as a result of covalent linking of drug to polymers. In this study, we reported on acid-liable dextran-doxorubicin (Dex-DOX) prodrug for controlled DOX release. Dextranhydrazine (Mw = 10 k Da) was prepared by reacting dextran p-nitrophenyl carbonate with tert-butoxycarbonylhydrazine (BocNHNH2), following with the removal of Boc-protective group. Anticancer drug DOX was then conjugated to the dextran via the formation of acid-labile hydrazone bond (Figure 1, A), which is stable at physiological pH but cleavable at endosomal pH. Unreacted or encapsulated DOX was removed by complete dialysis in DMSO and then in water. DOX loading capacity of Dex-DOX, defined as weight percentage of DOX in the prodrug, was determined to be 18.4 wt%. To confirm acid-sensitive DOX release from Dex-DOX, DOX release rate was measured at pH 5.5 and 7.4, respectively (Figure 1, B). As expected, Dex-DOX prodrug exhibited pHdependent DOX release profile. At pH 5.5, about 67% of DOX was released from the prodrug after 36 h. However, at pH 7.4, only 39% of DOX was liberated at the same time. This accelerated DOX release under acidic condition is ascribed to the degradation of acid-liable hydrazone bond. This result thus indicates the potential of Dex-DOX as an acid-sensitive prodrug for anti-cancer therapy.
Figure 1. (A) Chemical structure of Dex-DOX prodrug. (B) pH-dependent DOX release profile of Dex-DOX at pH 5.5 and 7.4.
This work was supported by the National Basic Research Program of China (973 Program No. 2011CB933402) and the China Natural Science Foundation (No. 21371117).
http://dx.doi.org/10.1016/j.nano.2015.12.285