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Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersome for tumor metastasis therapy
Abstracts / Journal of Controlled Release 213 (2015) e8–e152
In this study, hyaluronic acid (HA) and l-histidine (His) conjugate (HH), 25 kDa branched polyethylenimine (PEI25) and l-histidine (His) conjugate (PH) were constructed and used to form binary complexes for the co-delivery of gene and doxorubicin (DOX) (Scheme 1). HH, PH, gene and DOX could form stable nanoparticles via electrostatic and hydrophilic/hydrophobic interactions. The zeta potential and mean size of these nanoparticles were −32.1 mV and 245 nm, respectively. The polyelectrolyte complexes could efficiently protect DNA from DNAse degradation. Since HA could be recognized by CD44, which is overexpressed on cancer cells, targeted delivery could be achieved. Moreover, the imidazole ring of His could be protonated in tumor cells with low pH, and further destabilize the nanoparticles to release gene and DOX. The complexes showed high inhibition ratio and gene transfection efficiency in B16F10 cancer cells, but low cytotoxicity and gene transfection efficiency in NIH-3 T3 normal cells. These results suggest that the pHtriggered nanocarriers might be promising for synergistic cancer therapy.
e77
Tumor metastasis accounts for 90% of cancer-associated deaths and is almost inaccessible by chemotherapy, surgical operation or radiotherapy. Before distant spreading, metastasized cancers have invaded the lymphatic system as a first step in their progression [1]. Hence, effective control of the disease state of the lymphatics which drain a tumor site is crucial to treatment. Transdermal drug delivery could avoid the first-pass hepatic effect and fluctuation of blood concentration, and greatly facilitate drug accumulation in the lymphatics [2]. In this study, an amphiphilic hyaluronic acid (HA) derivative was assembled on the surface of a transfersome to form HA-T, which has a multilayered, spherical and highly flexible structure that facilitates transdermal penetration. The in vitro accumulative drug transdermal penetration of doxorubicin (DOX) loaded HA-T was 3 times higher than that of a solution of DOX. We established a transdermal administration animal model for qualitative and quantitative evaluation of HA-T tissue distribution. Compared with our previous transdermal formulation, nano-emulsion, HA-T significantly increases the transdermal penetration depth in rat skin and leads to higher accumulation in lymphatics in vivo, such as spleen and lymph nodes (Fig. 1). Most importantly, it exhibits desirable biocompatibility rather than the cytotoxicity of the emulsion. HA modified transfersomes were taken up effectively by breast tumor cells (MCF-7) via endocytosis, resulting in a 10 times higher cellular uptake ratios than the naked transfersome. HA-T holds a great potential in the treatment of cancer metastasis and also provides a new strategy in the development of nanomedicine for diagnosis and therapy of tumor metastasis.
Scheme 1. Schematic illustration of targeted co-delivery of gene and DOX based on HA–His/PEI–His polyelectrolyte complexes.
Keywords: hyaluronic acid, co-delivery, pH-triggered, CD44, DOX Acknowledgments This work was supported by the National Natural Science Foundation of China (51303068) and the Natural Science Fund of Jiangsu Province (BK2012557). References [1] D.W. Dong, X.R. Qi, pH-responsive complexes using prefunctionalized polymers for synchronous delivery of doxorubicin and siRNA to cancer cells, Biomaterials 34 (2013) 4849–4859. [2] Y.T. Chiang, C.L. Lo, pH-responsive polymer–liposomes for intracellular drug delivery and tumor extracellular matrix switched-on targeted cancer therapy, Biomaterials 35 (2014) 5414–5424. doi:10.1016/j.jconrel.2015.05.127
Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersome for tumor metastasis therapy Lin Hou, Ming Kong* College of Marine Life Science, Ocean University of China, Yushan Road, Qingdao, Shandong 266003, China ⁎Corresponding author. E-mail address: [email protected] (M. Kong).
Fig. 1. In vitro permeation of 1.0 mg/mL HA-Nanoemulsion (upper array) and DOX loaded HA-T (lower array) into mice abdominal skin after 4 h treatment (40×). Images were obtained in light and fluorescence mode with camera integration time set to 1 s. (green, FITC labeled HA; red, Dox).
Keywords: transdermal, transfersome, hyaluronic acid, lymphatic drug delivery, metastasis Acknowledgment This study is supported by grant from the NSFC (31300786) and Scientific Research Foundation for the Returned Overseas Chinese Scholars ([2013]693). References [1] S.K. Nune, P. Gunda, B.K. Majeti, P.K. Thallapally, M.L. Forrest, Advances in lymphatic imaging and drug delivery, Adv. Drug Deliver. Rev. 63 (2011) 876–885. [2] K.J. Hansen, Transdermal delivery of vaccines and therapeutic proteins, Pharm. Techn. 11 (2010) 14–20.
doi:10.1016/j.jconrel.2015.05.128
In this study, hyaluronic acid (HA) and l-histidine (His) conjugate (HH), 25 kDa branched polyethylenimine (PEI25) and l-histidine (His) conjugate (PH) were constructed and used to form binary complexes for the co-delivery of gene and doxorubicin (DOX) (Scheme 1). HH, PH, gene and DOX could form stable nanoparticles via electrostatic and hydrophilic/hydrophobic interactions. The zeta potential and mean size of these nanoparticles were −32.1 mV and 245 nm, respectively. The polyelectrolyte complexes could efficiently protect DNA from DNAse degradation. Since HA could be recognized by CD44, which is overexpressed on cancer cells, targeted delivery could be achieved. Moreover, the imidazole ring of His could be protonated in tumor cells with low pH, and further destabilize the nanoparticles to release gene and DOX. The complexes showed high inhibition ratio and gene transfection efficiency in B16F10 cancer cells, but low cytotoxicity and gene transfection efficiency in NIH-3 T3 normal cells. These results suggest that the pHtriggered nanocarriers might be promising for synergistic cancer therapy.
e77
Tumor metastasis accounts for 90% of cancer-associated deaths and is almost inaccessible by chemotherapy, surgical operation or radiotherapy. Before distant spreading, metastasized cancers have invaded the lymphatic system as a first step in their progression [1]. Hence, effective control of the disease state of the lymphatics which drain a tumor site is crucial to treatment. Transdermal drug delivery could avoid the first-pass hepatic effect and fluctuation of blood concentration, and greatly facilitate drug accumulation in the lymphatics [2]. In this study, an amphiphilic hyaluronic acid (HA) derivative was assembled on the surface of a transfersome to form HA-T, which has a multilayered, spherical and highly flexible structure that facilitates transdermal penetration. The in vitro accumulative drug transdermal penetration of doxorubicin (DOX) loaded HA-T was 3 times higher than that of a solution of DOX. We established a transdermal administration animal model for qualitative and quantitative evaluation of HA-T tissue distribution. Compared with our previous transdermal formulation, nano-emulsion, HA-T significantly increases the transdermal penetration depth in rat skin and leads to higher accumulation in lymphatics in vivo, such as spleen and lymph nodes (Fig. 1). Most importantly, it exhibits desirable biocompatibility rather than the cytotoxicity of the emulsion. HA modified transfersomes were taken up effectively by breast tumor cells (MCF-7) via endocytosis, resulting in a 10 times higher cellular uptake ratios than the naked transfersome. HA-T holds a great potential in the treatment of cancer metastasis and also provides a new strategy in the development of nanomedicine for diagnosis and therapy of tumor metastasis.
Scheme 1. Schematic illustration of targeted co-delivery of gene and DOX based on HA–His/PEI–His polyelectrolyte complexes.
Keywords: hyaluronic acid, co-delivery, pH-triggered, CD44, DOX Acknowledgments This work was supported by the National Natural Science Foundation of China (51303068) and the Natural Science Fund of Jiangsu Province (BK2012557). References [1] D.W. Dong, X.R. Qi, pH-responsive complexes using prefunctionalized polymers for synchronous delivery of doxorubicin and siRNA to cancer cells, Biomaterials 34 (2013) 4849–4859. [2] Y.T. Chiang, C.L. Lo, pH-responsive polymer–liposomes for intracellular drug delivery and tumor extracellular matrix switched-on targeted cancer therapy, Biomaterials 35 (2014) 5414–5424. doi:10.1016/j.jconrel.2015.05.127
Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersome for tumor metastasis therapy Lin Hou, Ming Kong* College of Marine Life Science, Ocean University of China, Yushan Road, Qingdao, Shandong 266003, China ⁎Corresponding author. E-mail address: [email protected] (M. Kong).
Fig. 1. In vitro permeation of 1.0 mg/mL HA-Nanoemulsion (upper array) and DOX loaded HA-T (lower array) into mice abdominal skin after 4 h treatment (40×). Images were obtained in light and fluorescence mode with camera integration time set to 1 s. (green, FITC labeled HA; red, Dox).
Keywords: transdermal, transfersome, hyaluronic acid, lymphatic drug delivery, metastasis Acknowledgment This study is supported by grant from the NSFC (31300786) and Scientific Research Foundation for the Returned Overseas Chinese Scholars ([2013]693). References [1] S.K. Nune, P. Gunda, B.K. Majeti, P.K. Thallapally, M.L. Forrest, Advances in lymphatic imaging and drug delivery, Adv. Drug Deliver. Rev. 63 (2011) 876–885. [2] K.J. Hansen, Transdermal delivery of vaccines and therapeutic proteins, Pharm. Techn. 11 (2010) 14–20.
doi:10.1016/j.jconrel.2015.05.128