Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery
Purpose In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF’s ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide...
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| Veröffentlicht in: | Pharmaceutical research 2013-07, Vol.30 (7), p.1799-1812 |
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| creator | Bareford, Lisa M. Avaritt, Brittany R. Ghandehari, Hamidreza Nan, Anjan Swaan, Peter W. |
| description | Purpose
In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF’s ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.
Methods
Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC
50
for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.
Results
Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC
50
values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.
Conclusion
Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity. |
| doi_str_mv | 10.1007/s11095-013-1024-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1364683836</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2987438621</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-30c0fb1c9cdbc7b819f06e876e59bf9980a46730995bbfe872975d78bbb5c5c13</originalsourceid><addsrcrecordid>eNp1kEtLAzEQgIMotlZ_gBdZEI-rk02ySW5qfUJBkQreQpImZct2tya7Qv-9kdbHxdMwM988-BA6xnCOAfhFxBgkywGTHENBc7aDhphxkkugb7toCDwVBad4gA5iXACAwJLuo0FBWClYQYbo8qUyra_1R9XkUx3mrnOz7Lmt10sXsnHbLPq57lzMfBuy6-B07LJpv0zJjaurDxfWh2jP6zq6o20code72-n4IZ883T-Orya5pVB0OQEL3mAr7cxYbtIfHkoneOmYNF5KAZqWnICUzBifGoXkbMaFMYZZZjEZodPN3lVo33sXO7Vo-9CkkwqTkpaCCFImCm8oG9oYg_NqFaqlDmuFQX05UxtnKjlTX84USzMn2829WbrZz8S3pAScbQEdra590I2t4i_HGVAmaOKKDRdTq5m78OfFf69_AhargwY</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1364683836</pqid></control><display><type>article</type><title>Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Bareford, Lisa M. ; Avaritt, Brittany R. ; Ghandehari, Hamidreza ; Nan, Anjan ; Swaan, Peter W.</creator><creatorcontrib>Bareford, Lisa M. ; Avaritt, Brittany R. ; Ghandehari, Hamidreza ; Nan, Anjan ; Swaan, Peter W.</creatorcontrib><description>Purpose
In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF’s ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.
Methods
Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC
50
for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.
Results
Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC
50
values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.
Conclusion
Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-013-1024-5</identifier><identifier>PMID: 23568523</identifier><identifier>CODEN: PHREEB</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Acrylamides - administration & dosage ; Acrylamides - chemistry ; Acrylamides - pharmacokinetics ; Acrylamides - pharmacology ; Antibiotics, Antineoplastic - administration & dosage ; Antibiotics, Antineoplastic - chemistry ; Antibiotics, Antineoplastic - pharmacokinetics ; Antibiotics, Antineoplastic - pharmacology ; Antineoplastic agents ; Biochemistry ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Breast - drug effects ; Breast cancer ; Breast Neoplasms - drug therapy ; Cell Line, Tumor ; Drug Delivery Systems ; Endocytosis ; Female ; General aspects ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Medical Law ; Medical sciences ; Mitomycin - administration & dosage ; Mitomycin - chemistry ; Mitomycin - pharmacokinetics ; Mitomycin - pharmacology ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Pharmaceutical sciences ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pharmacy ; Polymers ; Research Paper ; Riboflavin - metabolism ; Tumors ; Vitamin B</subject><ispartof>Pharmaceutical research, 2013-07, Vol.30 (7), p.1799-1812</ispartof><rights>Springer Science+Business Media New York 2013</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-30c0fb1c9cdbc7b819f06e876e59bf9980a46730995bbfe872975d78bbb5c5c13</citedby><cites>FETCH-LOGICAL-c402t-30c0fb1c9cdbc7b819f06e876e59bf9980a46730995bbfe872975d78bbb5c5c13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11095-013-1024-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11095-013-1024-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27504584$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23568523$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bareford, Lisa M.</creatorcontrib><creatorcontrib>Avaritt, Brittany R.</creatorcontrib><creatorcontrib>Ghandehari, Hamidreza</creatorcontrib><creatorcontrib>Nan, Anjan</creatorcontrib><creatorcontrib>Swaan, Peter W.</creatorcontrib><title>Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF’s ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.
Methods
Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC
50
for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.
Results
Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC
50
values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.
Conclusion
Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity.</description><subject>Acrylamides - administration & dosage</subject><subject>Acrylamides - chemistry</subject><subject>Acrylamides - pharmacokinetics</subject><subject>Acrylamides - pharmacology</subject><subject>Antibiotics, Antineoplastic - administration & dosage</subject><subject>Antibiotics, Antineoplastic - chemistry</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Breast - drug effects</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Cell Line, Tumor</subject><subject>Drug Delivery Systems</subject><subject>Endocytosis</subject><subject>Female</subject><subject>General aspects</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Mammary gland diseases</subject><subject>Medical Law</subject><subject>Medical sciences</subject><subject>Mitomycin - administration & dosage</subject><subject>Mitomycin - chemistry</subject><subject>Mitomycin - pharmacokinetics</subject><subject>Mitomycin - pharmacology</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Polymers</subject><subject>Research Paper</subject><subject>Riboflavin - metabolism</subject><subject>Tumors</subject><subject>Vitamin B</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kEtLAzEQgIMotlZ_gBdZEI-rk02ySW5qfUJBkQreQpImZct2tya7Qv-9kdbHxdMwM988-BA6xnCOAfhFxBgkywGTHENBc7aDhphxkkugb7toCDwVBad4gA5iXACAwJLuo0FBWClYQYbo8qUyra_1R9XkUx3mrnOz7Lmt10sXsnHbLPq57lzMfBuy6-B07LJpv0zJjaurDxfWh2jP6zq6o20code72-n4IZ883T-Orya5pVB0OQEL3mAr7cxYbtIfHkoneOmYNF5KAZqWnICUzBifGoXkbMaFMYZZZjEZodPN3lVo33sXO7Vo-9CkkwqTkpaCCFImCm8oG9oYg_NqFaqlDmuFQX05UxtnKjlTX84USzMn2829WbrZz8S3pAScbQEdra590I2t4i_HGVAmaOKKDRdTq5m78OfFf69_AhargwY</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Bareford, Lisa M.</creator><creator>Avaritt, Brittany R.</creator><creator>Ghandehari, Hamidreza</creator><creator>Nan, Anjan</creator><creator>Swaan, Peter W.</creator><general>Springer US</general><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></search><sort><creationdate>20130701</creationdate><title>Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery</title><author>Bareford, Lisa M. ; Avaritt, Brittany R. ; Ghandehari, Hamidreza ; Nan, Anjan ; Swaan, Peter W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-30c0fb1c9cdbc7b819f06e876e59bf9980a46730995bbfe872975d78bbb5c5c13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acrylamides - administration & dosage</topic><topic>Acrylamides - chemistry</topic><topic>Acrylamides - pharmacokinetics</topic><topic>Acrylamides - pharmacology</topic><topic>Antibiotics, Antineoplastic - administration & dosage</topic><topic>Antibiotics, Antineoplastic - chemistry</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Breast - drug effects</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Cell Line, Tumor</topic><topic>Drug Delivery Systems</topic><topic>Endocytosis</topic><topic>Female</topic><topic>General aspects</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Mammary gland diseases</topic><topic>Medical Law</topic><topic>Medical sciences</topic><topic>Mitomycin - administration & dosage</topic><topic>Mitomycin - chemistry</topic><topic>Mitomycin - pharmacokinetics</topic><topic>Mitomycin - pharmacology</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Polymers</topic><topic>Research Paper</topic><topic>Riboflavin - metabolism</topic><topic>Tumors</topic><topic>Vitamin B</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bareford, Lisa M.</creatorcontrib><creatorcontrib>Avaritt, Brittany R.</creatorcontrib><creatorcontrib>Ghandehari, Hamidreza</creatorcontrib><creatorcontrib>Nan, Anjan</creatorcontrib><creatorcontrib>Swaan, Peter W.</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><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bareford, Lisa M.</au><au>Avaritt, Brittany R.</au><au>Ghandehari, Hamidreza</au><au>Nan, Anjan</au><au>Swaan, Peter W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>30</volume><issue>7</issue><spage>1799</spage><epage>1812</epage><pages>1799-1812</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><coden>PHREEB</coden><abstract>Purpose
In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF’s ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.
Methods
Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC
50
for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.
Results
Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC
50
values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.
Conclusion
Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>23568523</pmid><doi>10.1007/s11095-013-1024-5</doi><tpages>14</tpages></addata></record> |
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| subjects | Acrylamides - administration & dosage Acrylamides - chemistry Acrylamides - pharmacokinetics Acrylamides - pharmacology Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - chemistry Antibiotics, Antineoplastic - pharmacokinetics Antibiotics, Antineoplastic - pharmacology Antineoplastic agents Biochemistry Biological and medical sciences Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Breast - drug effects Breast cancer Breast Neoplasms - drug therapy Cell Line, Tumor Drug Delivery Systems Endocytosis Female General aspects Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Medical Law Medical sciences Mitomycin - administration & dosage Mitomycin - chemistry Mitomycin - pharmacokinetics Mitomycin - pharmacology Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Pharmaceutical sciences Pharmacology. Drug treatments Pharmacology/Toxicology Pharmacy Polymers Research Paper Riboflavin - metabolism Tumors Vitamin B |
| title | Riboflavin-Targeted Polymer Conjugates for Breast Tumor Delivery |
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