Mannose-6-phosphate/insulin-like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells
The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively...
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| Veröffentlicht in: | Pharmaceutical research 2006-08, Vol.23 (8), p.1827-1834 |
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| creator | GREUPINK, Rick BAKKER, Hester I VAN GOOR, Harry DE BORST, Martin H BELJAARS, Leonie POELSTRA, Klaas |
| description | The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively deliver drugs to these cells.
We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.
M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.
M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA. |
| doi_str_mv | 10.1007/s11095-006-9025-2 |
| format | Article |
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We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.
M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.
M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-006-9025-2</identifier><identifier>PMID: 16850269</identifier><identifier>CODEN: PHREEB</identifier><language>eng</language><publisher>New York, NY: Springer</publisher><subject>3T3 Cells ; Animals ; Antibiotics, Antineoplastic - administration & dosage ; Antibiotics, Antineoplastic - pharmacology ; Binding, Competitive - drug effects ; Biochemistry ; Biological and medical sciences ; Capillaries - drug effects ; Capillaries - metabolism ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Common Bile Duct - physiology ; DNA - biosynthesis ; Dose-Response Relationship, Drug ; Drug Delivery Systems ; Electrophoresis, Polyacrylamide Gel ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Gene expression ; General pharmacology ; Immunohistochemistry ; Ligation ; Liver ; Liver Cirrhosis - pathology ; Male ; Mannosephosphates - metabolism ; Medical sciences ; Mice ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Mycophenolic Acid - administration & dosage ; Mycophenolic Acid - pharmacology ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology ; Pharmacology. Drug treatments ; Rats ; Rats, Wistar ; Receptor, IGF Type 2 - metabolism ; Renal Circulation - drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Rodents</subject><ispartof>Pharmaceutical research, 2006-08, Vol.23 (8), p.1827-1834</ispartof><rights>2006 INIST-CNRS</rights><rights>Springer Science+Business Media, Inc. 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-56d8101e07e5bcc0fef07cc27a67a0c65eb9e0167a6f9edb1a7dc3d58ede69a33</citedby><cites>FETCH-LOGICAL-c387t-56d8101e07e5bcc0fef07cc27a67a0c65eb9e0167a6f9edb1a7dc3d58ede69a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18082724$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16850269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GREUPINK, Rick</creatorcontrib><creatorcontrib>BAKKER, Hester I</creatorcontrib><creatorcontrib>VAN GOOR, Harry</creatorcontrib><creatorcontrib>DE BORST, Martin H</creatorcontrib><creatorcontrib>BELJAARS, Leonie</creatorcontrib><creatorcontrib>POELSTRA, Klaas</creatorcontrib><title>Mannose-6-phosphate/insulin-like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><description>The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively deliver drugs to these cells.
We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.
M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.
M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA.</description><subject>3T3 Cells</subject><subject>Animals</subject><subject>Antibiotics, Antineoplastic - administration & dosage</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Binding, Competitive - drug effects</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Capillaries - drug effects</subject><subject>Capillaries - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Common Bile Duct - physiology</subject><subject>DNA - biosynthesis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Delivery Systems</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Gene expression</subject><subject>General pharmacology</subject><subject>Immunohistochemistry</subject><subject>Ligation</subject><subject>Liver</subject><subject>Liver Cirrhosis - pathology</subject><subject>Male</subject><subject>Mannosephosphates - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Mycophenolic Acid - administration & dosage</subject><subject>Mycophenolic Acid - pharmacology</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptor, IGF Type 2 - metabolism</subject><subject>Renal Circulation - drug effects</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Rodents</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkkGL1DAUx4so7uzqB_AiQdBb3Je0adqjLKs7sOJFwVtI05dp1k5Sk1SZL-LnNcMMLHjx9PIPv_dI8ktVvWLwngHI68QY9IICtLQHLih_Um2YkHVJzfen1QYkb2gnG3ZRXab0AAAd65vn1QVrOwG87TfVn8_a-5CQtnSZQlomnfHa-bTOztPZ_UCyi-F3nojVJodIt1sS0eBS1ons9aGkJWJCn4kmWccdZmJDJHlCknBGk90vJCPOpcQDCZbsDyYsE_owO0O0cSPJgVg3xLBDX7YMznN6UT2zek748lyvqm8fb7_e3NH7L5-2Nx_uqak7malox44BQ5AoBmPAogVpDJe6lRpMK3DoEVgJre1xHJiWo6lH0eGIba_r-qp6d5q7xPBzxZTV3qXjCbTHsCbVdpwB581_QQ68aYSEAr75B3wIa_TlEorz8uSMSVEgdoJMDClFtGqJbq_jQTFQR7XqpFYVteqoVvHS8_o8eB32OD52nF0W4O0Z0Mno2UbtjUuPXAcdLx-i_guUsK8E</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>GREUPINK, Rick</creator><creator>BAKKER, Hester I</creator><creator>VAN GOOR, Harry</creator><creator>DE BORST, Martin H</creator><creator>BELJAARS, Leonie</creator><creator>POELSTRA, Klaas</creator><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060801</creationdate><title>Mannose-6-phosphate/insulin-like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells</title><author>GREUPINK, Rick ; BAKKER, Hester I ; VAN GOOR, Harry ; DE BORST, Martin H ; BELJAARS, Leonie ; POELSTRA, Klaas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-56d8101e07e5bcc0fef07cc27a67a0c65eb9e0167a6f9edb1a7dc3d58ede69a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>3T3 Cells</topic><topic>Animals</topic><topic>Antibiotics, Antineoplastic - administration & dosage</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Binding, Competitive - drug effects</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Capillaries - drug effects</topic><topic>Capillaries - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Common Bile Duct - physiology</topic><topic>DNA - biosynthesis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Delivery Systems</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Gene expression</topic><topic>General pharmacology</topic><topic>Immunohistochemistry</topic><topic>Ligation</topic><topic>Liver</topic><topic>Liver Cirrhosis - pathology</topic><topic>Male</topic><topic>Mannosephosphates - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Mycophenolic Acid - administration & dosage</topic><topic>Mycophenolic Acid - pharmacology</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptor, IGF Type 2 - metabolism</topic><topic>Renal Circulation - drug effects</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GREUPINK, Rick</creatorcontrib><creatorcontrib>BAKKER, Hester I</creatorcontrib><creatorcontrib>VAN GOOR, Harry</creatorcontrib><creatorcontrib>DE BORST, Martin H</creatorcontrib><creatorcontrib>BELJAARS, Leonie</creatorcontrib><creatorcontrib>POELSTRA, Klaas</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GREUPINK, Rick</au><au>BAKKER, Hester I</au><au>VAN GOOR, Harry</au><au>DE BORST, Martin H</au><au>BELJAARS, Leonie</au><au>POELSTRA, Klaas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mannose-6-phosphate/insulin-like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells</atitle><jtitle>Pharmaceutical research</jtitle><addtitle>Pharm Res</addtitle><date>2006-08-01</date><risdate>2006</risdate><volume>23</volume><issue>8</issue><spage>1827</spage><epage>1834</epage><pages>1827-1834</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><coden>PHREEB</coden><abstract>The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively deliver drugs to these cells.
We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.
M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.
M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA.</abstract><cop>New York, NY</cop><pub>Springer</pub><pmid>16850269</pmid><doi>10.1007/s11095-006-9025-2</doi><tpages>8</tpages></addata></record> |
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| subjects | 3T3 Cells Animals Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - pharmacology Binding, Competitive - drug effects Biochemistry Biological and medical sciences Capillaries - drug effects Capillaries - metabolism Cell Proliferation - drug effects Cell Survival - drug effects Common Bile Duct - physiology DNA - biosynthesis Dose-Response Relationship, Drug Drug Delivery Systems Electrophoresis, Polyacrylamide Gel Fibroblasts - drug effects Fibroblasts - metabolism Gene expression General pharmacology Immunohistochemistry Ligation Liver Liver Cirrhosis - pathology Male Mannosephosphates - metabolism Medical sciences Mice Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Mycophenolic Acid - administration & dosage Mycophenolic Acid - pharmacology Pharmaceutical technology. Pharmaceutical industry Pharmacology Pharmacology. Drug treatments Rats Rats, Wistar Receptor, IGF Type 2 - metabolism Renal Circulation - drug effects Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - biosynthesis RNA, Messenger - genetics Rodents |
| title | Mannose-6-phosphate/insulin-like growth factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells |
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