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Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
Purpose The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosu...
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| Published in: | Pharmaceutical research 2016-05, Vol.33 (5), p.1289-1303 |
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| container_end_page | 1303 |
| container_issue | 5 |
| container_start_page | 1289 |
| container_title | Pharmaceutical research |
| container_volume | 33 |
| creator | Fisusi, Funmilola A. Siew, Adeline Chooi, Kar Wai Okubanjo, Omotunde Garrett, Natalie Lalatsa, Katerina Serrano, Dolores Summers, Ian Moger, Julian Stapleton, Paul Satchi-Fainaro, Ronit Schätzlein, Andreas G Uchegbu, Ijeoma F. |
| description | Purpose
The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.
Methods
Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg
−1
) or ethanolic lomustine (6.5 mg kg
−1
) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg
−1
) or ethanolic lomustine (daily 1.2 mg kg
−1
- the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.
Results
The MET formulation resulted in modest brain targeting (brain/ bone AUC
0-4h
ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC
0-4h
ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.
Conclusions
Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity. |
| doi_str_mv | 10.1007/s11095-016-1872-x |
| format | article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4820487</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A747439048</galeid><sourcerecordid>A747439048</sourcerecordid><originalsourceid>FETCH-LOGICAL-c570t-a39566555138b0803cee05697c6ca3dfc9eb8a6ff12faa34e00b421124d35d813</originalsourceid><addsrcrecordid>eNp1ktFuFCEUhonR2G31AbwxJN54MxUGGJgbk3Wt1mTVi9bEO8IyZ6Y0M7CFmdpeNPEdfEOfRDa71tZoSCDhfP9PDudH6Bklh5QQ-SpRSmpREFoVVMmyuHqAZlRIVtSEf32IZkSWvFCS0z20n9I5IUTRmj9Ge2VVE0YEnaGbZRimNDoP-JPxYW3i6GwPCR95s-oBvwnjWd5y-aOJMXzDJxlxvsPGN_jYdbkYjfP4bZw6vIRL6BP--f0HnuOTMZoRumvchriDFsZbiPg0ghkH8GN6gh61pk_wdHceoC_vjk4Xx8Xy8_sPi_mysEKSsTCsFlUlhKBMrYgizAIQUdXSVtawprU1rJSp2paWrTGMAyErXlJa8oaJRlF2gF5vfdfTaoDG5rej6fU6usHEax2M0_cr3p3pLlxqrkrClcwGL3cGMVxMkEY9uGSh742HMCVNFRG8VrziGX3xF3oepuhze5pKqVilGC__UJ3pQTvfhvyu3ZjqueSSszxClanDf1B5NTA4m6fSunx_T0C3AhtDShHa2x4p0ZvM6G1mdM6M3mRGX2XN87ufc6v4HZIMlFsgrTejh3ino_-6_gI1scza</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1778368342</pqid></control><display><type>article</type><title>Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments</title><source>Springer Nature</source><creator>Fisusi, Funmilola A. ; Siew, Adeline ; Chooi, Kar Wai ; Okubanjo, Omotunde ; Garrett, Natalie ; Lalatsa, Katerina ; Serrano, Dolores ; Summers, Ian ; Moger, Julian ; Stapleton, Paul ; Satchi-Fainaro, Ronit ; Schätzlein, Andreas G ; Uchegbu, Ijeoma F.</creator><creatorcontrib>Fisusi, Funmilola A. ; Siew, Adeline ; Chooi, Kar Wai ; Okubanjo, Omotunde ; Garrett, Natalie ; Lalatsa, Katerina ; Serrano, Dolores ; Summers, Ian ; Moger, Julian ; Stapleton, Paul ; Satchi-Fainaro, Ronit ; Schätzlein, Andreas G ; Uchegbu, Ijeoma F.</creatorcontrib><description>Purpose
The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.
Methods
Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg
−1
) or ethanolic lomustine (6.5 mg kg
−1
) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg
−1
) or ethanolic lomustine (daily 1.2 mg kg
−1
- the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.
Results
The MET formulation resulted in modest brain targeting (brain/ bone AUC
0-4h
ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC
0-4h
ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.
Conclusions
Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1007/s11095-016-1872-x</identifier><identifier>PMID: 26903051</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Antineoplastic Agents, Alkylating - administration & dosage ; Antineoplastic Agents, Alkylating - adverse effects ; Antineoplastic Agents, Alkylating - pharmacokinetics ; Antineoplastic Agents, Alkylating - therapeutic use ; Biochemistry ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Biomedicine ; Bone marrow ; Bone Marrow - drug effects ; Bone Marrow - metabolism ; Bone Marrow - pathology ; Brain - drug effects ; Brain - metabolism ; Brain - pathology ; Brain cancer ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain tumors ; Cancer ; Cell Line, Tumor ; Chemotherapy ; Drug Delivery Systems ; Drug therapy ; Ethylenediaminetetraacetic acid ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Gliomas ; Health aspects ; Humans ; Lomustine ; Lomustine - administration & dosage ; Lomustine - adverse effects ; Lomustine - pharmacokinetics ; Lomustine - therapeutic use ; Male ; Medical Law ; Mice ; Nanoparticles ; Nanoparticles - chemistry ; Pharmaceutical sciences ; Pharmacology/Toxicology ; Pharmacy ; Research Paper ; Tumors</subject><ispartof>Pharmaceutical research, 2016-05, Vol.33 (5), p.1289-1303</ispartof><rights>The Author(s) 2016</rights><rights>COPYRIGHT 2016 Springer</rights><rights>Springer Science+Business Media New York 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c570t-a39566555138b0803cee05697c6ca3dfc9eb8a6ff12faa34e00b421124d35d813</citedby><cites>FETCH-LOGICAL-c570t-a39566555138b0803cee05697c6ca3dfc9eb8a6ff12faa34e00b421124d35d813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26903051$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fisusi, Funmilola A.</creatorcontrib><creatorcontrib>Siew, Adeline</creatorcontrib><creatorcontrib>Chooi, Kar Wai</creatorcontrib><creatorcontrib>Okubanjo, Omotunde</creatorcontrib><creatorcontrib>Garrett, Natalie</creatorcontrib><creatorcontrib>Lalatsa, Katerina</creatorcontrib><creatorcontrib>Serrano, Dolores</creatorcontrib><creatorcontrib>Summers, Ian</creatorcontrib><creatorcontrib>Moger, Julian</creatorcontrib><creatorcontrib>Stapleton, Paul</creatorcontrib><creatorcontrib>Satchi-Fainaro, Ronit</creatorcontrib><creatorcontrib>Schätzlein, Andreas G</creatorcontrib><creatorcontrib>Uchegbu, Ijeoma F.</creatorcontrib><title>Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><addtitle>Pharm Res</addtitle><description>Purpose
The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.
Methods
Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg
−1
) or ethanolic lomustine (6.5 mg kg
−1
) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg
−1
) or ethanolic lomustine (daily 1.2 mg kg
−1
- the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.
Results
The MET formulation resulted in modest brain targeting (brain/ bone AUC
0-4h
ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC
0-4h
ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.
Conclusions
Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.</description><subject>Animals</subject><subject>Antineoplastic Agents, Alkylating - administration & dosage</subject><subject>Antineoplastic Agents, Alkylating - adverse effects</subject><subject>Antineoplastic Agents, Alkylating - pharmacokinetics</subject><subject>Antineoplastic Agents, Alkylating - therapeutic use</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering and Bioengineering</subject><subject>Biomedicine</subject><subject>Bone marrow</subject><subject>Bone Marrow - drug effects</subject><subject>Bone Marrow - metabolism</subject><subject>Bone Marrow - pathology</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain tumors</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Drug Delivery Systems</subject><subject>Drug therapy</subject><subject>Ethylenediaminetetraacetic acid</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - pathology</subject><subject>Gliomas</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Lomustine</subject><subject>Lomustine - administration & dosage</subject><subject>Lomustine - adverse effects</subject><subject>Lomustine - pharmacokinetics</subject><subject>Lomustine - therapeutic use</subject><subject>Male</subject><subject>Medical Law</subject><subject>Mice</subject><subject>Nanoparticles</subject><subject>Nanoparticles - chemistry</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Research Paper</subject><subject>Tumors</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp1ktFuFCEUhonR2G31AbwxJN54MxUGGJgbk3Wt1mTVi9bEO8IyZ6Y0M7CFmdpeNPEdfEOfRDa71tZoSCDhfP9PDudH6Bklh5QQ-SpRSmpREFoVVMmyuHqAZlRIVtSEf32IZkSWvFCS0z20n9I5IUTRmj9Ge2VVE0YEnaGbZRimNDoP-JPxYW3i6GwPCR95s-oBvwnjWd5y-aOJMXzDJxlxvsPGN_jYdbkYjfP4bZw6vIRL6BP--f0HnuOTMZoRumvchriDFsZbiPg0ghkH8GN6gh61pk_wdHceoC_vjk4Xx8Xy8_sPi_mysEKSsTCsFlUlhKBMrYgizAIQUdXSVtawprU1rJSp2paWrTGMAyErXlJa8oaJRlF2gF5vfdfTaoDG5rej6fU6usHEax2M0_cr3p3pLlxqrkrClcwGL3cGMVxMkEY9uGSh742HMCVNFRG8VrziGX3xF3oepuhze5pKqVilGC__UJ3pQTvfhvyu3ZjqueSSszxClanDf1B5NTA4m6fSunx_T0C3AhtDShHa2x4p0ZvM6G1mdM6M3mRGX2XN87ufc6v4HZIMlFsgrTejh3ino_-6_gI1scza</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Fisusi, Funmilola A.</creator><creator>Siew, Adeline</creator><creator>Chooi, Kar Wai</creator><creator>Okubanjo, Omotunde</creator><creator>Garrett, Natalie</creator><creator>Lalatsa, Katerina</creator><creator>Serrano, Dolores</creator><creator>Summers, Ian</creator><creator>Moger, Julian</creator><creator>Stapleton, Paul</creator><creator>Satchi-Fainaro, Ronit</creator><creator>Schätzlein, Andreas G</creator><creator>Uchegbu, Ijeoma F.</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</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>5PM</scope></search><sort><creationdate>20160501</creationdate><title>Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments</title><author>Fisusi, Funmilola A. ; Siew, Adeline ; Chooi, Kar Wai ; Okubanjo, Omotunde ; Garrett, Natalie ; Lalatsa, Katerina ; Serrano, Dolores ; Summers, Ian ; Moger, Julian ; Stapleton, Paul ; Satchi-Fainaro, Ronit ; Schätzlein, Andreas G ; Uchegbu, Ijeoma F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c570t-a39566555138b0803cee05697c6ca3dfc9eb8a6ff12faa34e00b421124d35d813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents, Alkylating - administration & dosage</topic><topic>Antineoplastic Agents, Alkylating - adverse effects</topic><topic>Antineoplastic Agents, Alkylating - pharmacokinetics</topic><topic>Antineoplastic Agents, Alkylating - therapeutic use</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering and Bioengineering</topic><topic>Biomedicine</topic><topic>Bone marrow</topic><topic>Bone Marrow - drug effects</topic><topic>Bone Marrow - metabolism</topic><topic>Bone Marrow - pathology</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain tumors</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Chemotherapy</topic><topic>Drug Delivery Systems</topic><topic>Drug therapy</topic><topic>Ethylenediaminetetraacetic acid</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Gliomas</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Lomustine</topic><topic>Lomustine - administration & dosage</topic><topic>Lomustine - adverse effects</topic><topic>Lomustine - pharmacokinetics</topic><topic>Lomustine - therapeutic use</topic><topic>Male</topic><topic>Medical Law</topic><topic>Mice</topic><topic>Nanoparticles</topic><topic>Nanoparticles - chemistry</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Research Paper</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fisusi, Funmilola A.</creatorcontrib><creatorcontrib>Siew, Adeline</creatorcontrib><creatorcontrib>Chooi, Kar Wai</creatorcontrib><creatorcontrib>Okubanjo, Omotunde</creatorcontrib><creatorcontrib>Garrett, Natalie</creatorcontrib><creatorcontrib>Lalatsa, Katerina</creatorcontrib><creatorcontrib>Serrano, Dolores</creatorcontrib><creatorcontrib>Summers, Ian</creatorcontrib><creatorcontrib>Moger, Julian</creatorcontrib><creatorcontrib>Stapleton, Paul</creatorcontrib><creatorcontrib>Satchi-Fainaro, Ronit</creatorcontrib><creatorcontrib>Schätzlein, Andreas G</creatorcontrib><creatorcontrib>Uchegbu, Ijeoma F.</creatorcontrib><collection>Springer Nature OA Free Journals</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)</collection><collection>ProQuest Central</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>PubMed Central (Full Participant titles)</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fisusi, Funmilola A.</au><au>Siew, Adeline</au><au>Chooi, Kar Wai</au><au>Okubanjo, Omotunde</au><au>Garrett, Natalie</au><au>Lalatsa, Katerina</au><au>Serrano, Dolores</au><au>Summers, Ian</au><au>Moger, Julian</au><au>Stapleton, Paul</au><au>Satchi-Fainaro, Ronit</au><au>Schätzlein, Andreas G</au><au>Uchegbu, Ijeoma F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments</atitle><jtitle>Pharmaceutical research</jtitle><stitle>Pharm Res</stitle><addtitle>Pharm Res</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>33</volume><issue>5</issue><spage>1289</spage><epage>1303</epage><pages>1289-1303</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><abstract>Purpose
The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.
Methods
Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg
−1
) or ethanolic lomustine (6.5 mg kg
−1
) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg
−1
) or ethanolic lomustine (daily 1.2 mg kg
−1
- the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.
Results
The MET formulation resulted in modest brain targeting (brain/ bone AUC
0-4h
ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC
0-4h
ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.
Conclusions
Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>26903051</pmid><doi>10.1007/s11095-016-1872-x</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0724-8741 |
| ispartof | Pharmaceutical research, 2016-05, Vol.33 (5), p.1289-1303 |
| issn | 0724-8741 1573-904X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4820487 |
| source | Springer Nature |
| subjects | Animals Antineoplastic Agents, Alkylating - administration & dosage Antineoplastic Agents, Alkylating - adverse effects Antineoplastic Agents, Alkylating - pharmacokinetics Antineoplastic Agents, Alkylating - therapeutic use Biochemistry Biomedical and Life Sciences Biomedical Engineering and Bioengineering Biomedicine Bone marrow Bone Marrow - drug effects Bone Marrow - metabolism Bone Marrow - pathology Brain - drug effects Brain - metabolism Brain - pathology Brain cancer Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain tumors Cancer Cell Line, Tumor Chemotherapy Drug Delivery Systems Drug therapy Ethylenediaminetetraacetic acid Glioblastoma - drug therapy Glioblastoma - metabolism Glioblastoma - pathology Gliomas Health aspects Humans Lomustine Lomustine - administration & dosage Lomustine - adverse effects Lomustine - pharmacokinetics Lomustine - therapeutic use Male Medical Law Mice Nanoparticles Nanoparticles - chemistry Pharmaceutical sciences Pharmacology/Toxicology Pharmacy Research Paper Tumors |
| title | Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments |
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