LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma

Abstract Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood–brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decorati...

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Veröffentlicht in:Biomaterials 2013-12, Vol.34 (36), p.9171-9182
Hauptverfasser: Zhang, Bo, Sun, Xiyang, Mei, Heng, Wang, Yu, Liao, Ziwei, Chen, Jun, Zhang, Qizhi, Hu, Yu, Pang, Zhiqing, Jiang, Xinguo
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container_end_page 9182
container_issue 36
container_start_page 9171
container_title Biomaterials
container_volume 34
creator Zhang, Bo
Sun, Xiyang
Mei, Heng
Wang, Yu
Liao, Ziwei
Chen, Jun
Zhang, Qizhi
Hu, Yu
Pang, Zhiqing
Jiang, Xinguo
description Abstract Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood–brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP–PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP–PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP–PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.
doi_str_mv 10.1016/j.biomaterials.2013.08.039
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To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP–PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP–PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&amp;E staining showed that PNP–PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.</description><identifier>ISSN: 0142-9612</identifier><identifier>EISSN: 1878-5905</identifier><identifier>DOI: 10.1016/j.biomaterials.2013.08.039</identifier><identifier>PMID: 24008043</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Advanced Basic Science ; Animals ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Brain glioma ; Brain Neoplasms - drug therapy ; Dentistry ; Drug Delivery Systems ; Dual targeting ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Fluorescence ; Glioma - drug therapy ; In Situ Nick-End Labeling ; Kaplan-Meier Estimate ; Low-density lipoprotein receptor ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nanoparticles ; Nanoparticles - chemistry ; Nanoparticles - ultrastructure ; Particle Size ; Peptide-22 ; Peptides - pharmacology ; Peptides - therapeutic use ; Rats ; Receptors, LDL - metabolism ; Static Electricity ; Targeting therapy ; Tissue Distribution - drug effects</subject><ispartof>Biomaterials, 2013-12, Vol.34 (36), p.9171-9182</ispartof><rights>Elsevier Ltd</rights><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-191d65840097fd3720750f0932e7411b17a1ed92470747aab62e8036c97572813</citedby><cites>FETCH-LOGICAL-c435t-191d65840097fd3720750f0932e7411b17a1ed92470747aab62e8036c97572813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.biomaterials.2013.08.039$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24008043$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Sun, Xiyang</creatorcontrib><creatorcontrib>Mei, Heng</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Liao, Ziwei</creatorcontrib><creatorcontrib>Chen, Jun</creatorcontrib><creatorcontrib>Zhang, Qizhi</creatorcontrib><creatorcontrib>Hu, Yu</creatorcontrib><creatorcontrib>Pang, Zhiqing</creatorcontrib><creatorcontrib>Jiang, Xinguo</creatorcontrib><title>LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma</title><title>Biomaterials</title><addtitle>Biomaterials</addtitle><description>Abstract Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood–brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP–PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP–PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&amp;E staining showed that PNP–PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. 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To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP–PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP–PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&amp;E staining showed that PNP–PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>24008043</pmid><doi>10.1016/j.biomaterials.2013.08.039</doi><tpages>12</tpages></addata></record>
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identifier ISSN: 0142-9612
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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Advanced Basic Science
Animals
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - metabolism
Brain glioma
Brain Neoplasms - drug therapy
Dentistry
Drug Delivery Systems
Dual targeting
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Fluorescence
Glioma - drug therapy
In Situ Nick-End Labeling
Kaplan-Meier Estimate
Low-density lipoprotein receptor
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Nanoparticles
Nanoparticles - chemistry
Nanoparticles - ultrastructure
Particle Size
Peptide-22
Peptides - pharmacology
Peptides - therapeutic use
Rats
Receptors, LDL - metabolism
Static Electricity
Targeting therapy
Tissue Distribution - drug effects
title LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma
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