- Email: [email protected]
Local transdermal delivery of 10,11-methylenedioxycamptothecin by nanoemulsion for breast cancer prevention
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Abstracts / Journal of Controlled Release 259 (2017) e5–e195
b
Suzhou Ribo Life Science Co. Ltd., Jiangsu 215300, China ⁎Correspondence to: Y. Huang, Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing, 100081, China. ⁎⁎Corresponding author. E-mail addresses: [email protected] (Y. Huang), [email protected] (S. Gao) Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years [1]. Ribonucleotide reductase is a ratelimiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication [2]. Here, siRNA targeting RRM2, the second subunit of ribonucleotide reductase, was used to inhibit tumor cell growth both in vitro and in vivo. Accordingly, cell morphology, colony formation, cell cycle arrest, cell proliferation (in vitro) and tumor growth (in vivo) were investigated. First, we designed 23 siRNAs against RRM2 and one of them (termed siRRM2) with high potency and well RNase-resistant capability was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times than applying DOX alone, suggesting a well synergistic effect of siRRM2 and DOX on PANC-1 cells. Moreover, combination of siRRM2 and DOX significantly suppressed the tumor growth on the PANC-1xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a drugable siRNA, a feasible target gene and a promising therapeutic method for the treatment of pancreatic cancer.
[2] S.J. Elledge, Z. Zhou, J.B. Allen, Ribonucleotide reductase: regulation, regulation, regulation, Trends Biochem. Sci. 17 (1992) 119-123.
doi:10.1016/j.jconrel.2017.03.355
Local transdermal delivery of 10,11-methylenedioxycamptothecin by nanoemulsion for breast cancer prevention Yuanyuan Gaoa, Weifen Zhanga, Tongyi Sunb,⁎ a College of Pharmacy, Weifang Medical University, Weifang 261053, China b School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China ⁎Corresponding author. E-mail addresses: [email protected] (Y. Gao), [email protected] (T. Sun) Breast cancer, the most common cancer affecting females, accounts for 16% of all kinds of women tumors [1]. 10,11-Methylenedioxycamptothecin (MD-CPT) is a promising candidate molecule in breast cancer chemotherapy. Low-toxic, well-tolerated preventive therapy to treat the breast cancer is needed. This study designed a mild non-invasive transdermal delivery system targeting to the breast tumor. An amphiphilic hyaluronic acid derivative was assembled to form an O/W type nanoemulsion (HAN). MD-CPT loaded HAN (M-HAN) had a high flexible structure as well as desirable penetrability across human breast skin. M-HAN could be successfully endocytosed by MCF-7, which resulted in the transportation of MD-CPT into nucleus. The cells were arrested at G1/S stage and failed into mitosis. The in vivo local delivery efficacy of M-HAN was evaluated in tumor-bearing mice. The drug tissue distribution demonstrated that M-HAN improved the drug retention, reduced medicine residues, and increased the bioavailability and tumor accumulation. The reduced systemic toxicity of MD-CPT encapsulated by HAN was revealed by body weight measure of the mice. Overall, our device could be potentially extended to the delivery of a multiplicity of drugs to preserve organ function and improve the tolerability.
Fig. 1. Illustration of siRNA-loaded lipid nanoparticle (LNP) (left) and the tumor growth inhibition in vivo (right).
Keywords: siRNA, doxorubicin, pancreatic cancer, liposome Acknowledgements This work was supported by the National Natural Science Foundation of China (81402863), the Postdoctoral Science Foundation of China (2014M550008 and 2015T80016), the National Drug Program of China (2015ZX09102-023-002 and 2014ZX09304313-001), and the Natural Science Foundation of Jiangsu Province (BK2011381). References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2016, CA Cancer J. Clin. 66 (2016) 7-30.
Fig. 1. Illustration of MD-CPT loaded HAN transdermal delivery to the tumor cell.
Keywords: hyaluronic acid, nanoemulsion, 10,11-Methylenedioxy-camptothecin, transdermal delivery system, breast cancer
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Acknowledgements The National Natural Science Foundation of China (81573717), the Natural Science Foundation of Shandong Province (ZR2015HL056), the Development Project of Science and Technology for Medicine and Health of Shandong Province (2015WS0059), the Colleges and Universities Science and Technology Planning Project of Shandong province (J15LM10). Reference [1] S. A. Tawde, L. Chablani, A. Akalkotkar, M. J D’Souza, Evaluation of microparticulate ovarian cancer vaccine via transdermal route of delivery, J. Control. Release 235 (2016) 147-154.
doi:10.1016/j.jconrel.2017.03.356
e181
for enhanced photo-activated therapy (Fig. 1). A hydrophobic Pt(N3) was grafted to the sidechains of hydrophilic dextran, and the obtained amphiphilic Dex–Pt(N3) conjugates self-assembled into nanoparticles for further Cur encapsulation. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant ROS from Cur for fast PDT and release lasting Pt(II) from Pt(N3) for longacting PCT. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photo-activated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future. Keywords: photoactivated therapy, photodynamic therapy, photochemotherapy, nanoparticles, cancer, co-delivery
Single-stimulus dual-drug sensitive nanoplatform for enhanced photoactivated therapy Shasha He, Dongfang Zhou, Yubin Huang⁎ State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China ⁎Corresponding author. E-mail address: [email protected] (Y. Huang) Photoactivated therapies have become complementary and attractive modality for traditional cancer treatment [1]. Due to the complexity of tumor including multi-drug resistance and heterogeneity, usually a single photo-activated therapy remains suboptimal [2]. When applied with light, photosensitizer (PS) for photodynamic therapy (PDT) would generate reactive oxygen species (ROS) with a short life-time less than 40 ns for instant cell-killing, and photoactivated metal chemotherapeutic drug (PCD) for photochemotherapy (PCT) would release active chemotherapeutic drug for lasting cell-killing. Therefore, combination of fast PDT and long-acting PCT should be an attractive strategy for more effective cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nano-platform, Cur-loaded Dex–Pt(N3) nanoparticles (Cur@DPNs)
Fig. 1. Preparation and single-stimulus (light) dual-drug sensitivity of Cur@DPNs.
Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (No. 51403198 and 51573069). References [1] M. Ethirajan, Y. Chen, P. Joshi, R.K. Pandey, The role of porphyrin chemistry in tumor imaging and photodynamic therapy, Chem. Soc. Rev. 40 (2011) 340-362. [2] Q. Yin, J. Shen, Z. Zhang, H. Yu, Y. Li, Reversal of multidrug resistance by stimuliresponsive drug delivery systems for therapy of tumor, Adv. Drug. Delivery. Rev. 65 (2013) 1699-1715.
doi:10.1016/j.jconrel.2017.03.357
Co-delivery of angiostatin and curcumin by a biodegradable polymersome for antiangiogenic therapy Yue Cao, Yan Li, Wenliang Li, Luguo Sun, Yongli Bao, Yuxin Li⁎ School of Life Sciences, Northeast Normal University, Changchun 130024, China ⁎Corresponding author. E-mail addresses: [email protected] (Y. Cao), [email protected] (Y. Li) Angiostatin is one of the first few endogenous antiangiogenic agents that are able to restrain tumor growth and transfer through inhibition of endothelial cell proliferation and migration [1]. However, the clinical application of angiostatin has been limited by its own shortcomings, such as short half-life, instability, high price, etc. Recently, polymersomes (PMs) have emerged as a novel class of nanocarriers, which could be employed to encapsulate both hydrophilic drug in their aqueous cores and hydrophobic drugs in their membrane simultaneously [2]. Hence, polymersomes have a great potential for combination therapy [3]. In this work, polymersomes based on poly (ethylene glycol)-bpoly (ε-caprolactone) (PEG-PCL-PMs) were prepared by film hydration method for the co-encapsulation and controlled delivery of both angiostatin and curcumin (Fig. 1). Confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) were employed to confirm the polymersomal structures of PEG-PCL-PMs. MTT assay displayed that dual drug-loaded polymersomes (AS-CurPMs) can remarkably inhibit proliferation of HMEC-1 cells compared to single drug-loaded polymersomes. The chick chorioallantoic membrane (CAM) assay showed that AS-Cur-PMs could significantly decrease vessel sprouting, indicating that AS-Cur-PMs could inhibit angiognesis effectively.
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
b
Suzhou Ribo Life Science Co. Ltd., Jiangsu 215300, China ⁎Correspondence to: Y. Huang, Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing, 100081, China. ⁎⁎Corresponding author. E-mail addresses: [email protected] (Y. Huang), [email protected] (S. Gao) Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years [1]. Ribonucleotide reductase is a ratelimiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication [2]. Here, siRNA targeting RRM2, the second subunit of ribonucleotide reductase, was used to inhibit tumor cell growth both in vitro and in vivo. Accordingly, cell morphology, colony formation, cell cycle arrest, cell proliferation (in vitro) and tumor growth (in vivo) were investigated. First, we designed 23 siRNAs against RRM2 and one of them (termed siRRM2) with high potency and well RNase-resistant capability was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times than applying DOX alone, suggesting a well synergistic effect of siRRM2 and DOX on PANC-1 cells. Moreover, combination of siRRM2 and DOX significantly suppressed the tumor growth on the PANC-1xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a drugable siRNA, a feasible target gene and a promising therapeutic method for the treatment of pancreatic cancer.
[2] S.J. Elledge, Z. Zhou, J.B. Allen, Ribonucleotide reductase: regulation, regulation, regulation, Trends Biochem. Sci. 17 (1992) 119-123.
doi:10.1016/j.jconrel.2017.03.355
Local transdermal delivery of 10,11-methylenedioxycamptothecin by nanoemulsion for breast cancer prevention Yuanyuan Gaoa, Weifen Zhanga, Tongyi Sunb,⁎ a College of Pharmacy, Weifang Medical University, Weifang 261053, China b School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China ⁎Corresponding author. E-mail addresses: [email protected] (Y. Gao), [email protected] (T. Sun) Breast cancer, the most common cancer affecting females, accounts for 16% of all kinds of women tumors [1]. 10,11-Methylenedioxycamptothecin (MD-CPT) is a promising candidate molecule in breast cancer chemotherapy. Low-toxic, well-tolerated preventive therapy to treat the breast cancer is needed. This study designed a mild non-invasive transdermal delivery system targeting to the breast tumor. An amphiphilic hyaluronic acid derivative was assembled to form an O/W type nanoemulsion (HAN). MD-CPT loaded HAN (M-HAN) had a high flexible structure as well as desirable penetrability across human breast skin. M-HAN could be successfully endocytosed by MCF-7, which resulted in the transportation of MD-CPT into nucleus. The cells were arrested at G1/S stage and failed into mitosis. The in vivo local delivery efficacy of M-HAN was evaluated in tumor-bearing mice. The drug tissue distribution demonstrated that M-HAN improved the drug retention, reduced medicine residues, and increased the bioavailability and tumor accumulation. The reduced systemic toxicity of MD-CPT encapsulated by HAN was revealed by body weight measure of the mice. Overall, our device could be potentially extended to the delivery of a multiplicity of drugs to preserve organ function and improve the tolerability.
Fig. 1. Illustration of siRNA-loaded lipid nanoparticle (LNP) (left) and the tumor growth inhibition in vivo (right).
Keywords: siRNA, doxorubicin, pancreatic cancer, liposome Acknowledgements This work was supported by the National Natural Science Foundation of China (81402863), the Postdoctoral Science Foundation of China (2014M550008 and 2015T80016), the National Drug Program of China (2015ZX09102-023-002 and 2014ZX09304313-001), and the Natural Science Foundation of Jiangsu Province (BK2011381). References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2016, CA Cancer J. Clin. 66 (2016) 7-30.
Fig. 1. Illustration of MD-CPT loaded HAN transdermal delivery to the tumor cell.
Keywords: hyaluronic acid, nanoemulsion, 10,11-Methylenedioxy-camptothecin, transdermal delivery system, breast cancer
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
Acknowledgements The National Natural Science Foundation of China (81573717), the Natural Science Foundation of Shandong Province (ZR2015HL056), the Development Project of Science and Technology for Medicine and Health of Shandong Province (2015WS0059), the Colleges and Universities Science and Technology Planning Project of Shandong province (J15LM10). Reference [1] S. A. Tawde, L. Chablani, A. Akalkotkar, M. J D’Souza, Evaluation of microparticulate ovarian cancer vaccine via transdermal route of delivery, J. Control. Release 235 (2016) 147-154.
doi:10.1016/j.jconrel.2017.03.356
e181
for enhanced photo-activated therapy (Fig. 1). A hydrophobic Pt(N3) was grafted to the sidechains of hydrophilic dextran, and the obtained amphiphilic Dex–Pt(N3) conjugates self-assembled into nanoparticles for further Cur encapsulation. The developed Cur@DPNs could be photoactivated by UVA light to simultaneously generate instant ROS from Cur for fast PDT and release lasting Pt(II) from Pt(N3) for longacting PCT. Compared with small free drugs and individual photoactivated therapy, Cur@DPNs exhibited enhanced photo-activated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future. Keywords: photoactivated therapy, photodynamic therapy, photochemotherapy, nanoparticles, cancer, co-delivery
Single-stimulus dual-drug sensitive nanoplatform for enhanced photoactivated therapy Shasha He, Dongfang Zhou, Yubin Huang⁎ State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China ⁎Corresponding author. E-mail address: [email protected] (Y. Huang) Photoactivated therapies have become complementary and attractive modality for traditional cancer treatment [1]. Due to the complexity of tumor including multi-drug resistance and heterogeneity, usually a single photo-activated therapy remains suboptimal [2]. When applied with light, photosensitizer (PS) for photodynamic therapy (PDT) would generate reactive oxygen species (ROS) with a short life-time less than 40 ns for instant cell-killing, and photoactivated metal chemotherapeutic drug (PCD) for photochemotherapy (PCT) would release active chemotherapeutic drug for lasting cell-killing. Therefore, combination of fast PDT and long-acting PCT should be an attractive strategy for more effective cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nano-platform, Cur-loaded Dex–Pt(N3) nanoparticles (Cur@DPNs)
Fig. 1. Preparation and single-stimulus (light) dual-drug sensitivity of Cur@DPNs.
Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (No. 51403198 and 51573069). References [1] M. Ethirajan, Y. Chen, P. Joshi, R.K. Pandey, The role of porphyrin chemistry in tumor imaging and photodynamic therapy, Chem. Soc. Rev. 40 (2011) 340-362. [2] Q. Yin, J. Shen, Z. Zhang, H. Yu, Y. Li, Reversal of multidrug resistance by stimuliresponsive drug delivery systems for therapy of tumor, Adv. Drug. Delivery. Rev. 65 (2013) 1699-1715.
doi:10.1016/j.jconrel.2017.03.357
Co-delivery of angiostatin and curcumin by a biodegradable polymersome for antiangiogenic therapy Yue Cao, Yan Li, Wenliang Li, Luguo Sun, Yongli Bao, Yuxin Li⁎ School of Life Sciences, Northeast Normal University, Changchun 130024, China ⁎Corresponding author. E-mail addresses: [email protected] (Y. Cao), [email protected] (Y. Li) Angiostatin is one of the first few endogenous antiangiogenic agents that are able to restrain tumor growth and transfer through inhibition of endothelial cell proliferation and migration [1]. However, the clinical application of angiostatin has been limited by its own shortcomings, such as short half-life, instability, high price, etc. Recently, polymersomes (PMs) have emerged as a novel class of nanocarriers, which could be employed to encapsulate both hydrophilic drug in their aqueous cores and hydrophobic drugs in their membrane simultaneously [2]. Hence, polymersomes have a great potential for combination therapy [3]. In this work, polymersomes based on poly (ethylene glycol)-bpoly (ε-caprolactone) (PEG-PCL-PMs) were prepared by film hydration method for the co-encapsulation and controlled delivery of both angiostatin and curcumin (Fig. 1). Confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) were employed to confirm the polymersomal structures of PEG-PCL-PMs. MTT assay displayed that dual drug-loaded polymersomes (AS-CurPMs) can remarkably inhibit proliferation of HMEC-1 cells compared to single drug-loaded polymersomes. The chick chorioallantoic membrane (CAM) assay showed that AS-Cur-PMs could significantly decrease vessel sprouting, indicating that AS-Cur-PMs could inhibit angiognesis effectively.