Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration
To assess targeting of an epothilone folate conjugate (BMS-753493) to the folate receptor (FR)-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA) and LC–MS/MS following i.v. administration of BMS-75349...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-09-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383516301058 |
| _version_ | 1818422342256164864 |
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| author | Hong Shen Lifei Wang Weiqi Chen Krista Menard Yang Hong Yuan Tian Samuel J. Bonacorsi W. Griffith Humphreys Francis Y. Lee Jinping Gan |
| author_facet | Hong Shen Lifei Wang Weiqi Chen Krista Menard Yang Hong Yuan Tian Samuel J. Bonacorsi W. Griffith Humphreys Francis Y. Lee Jinping Gan |
| author_sort | Hong Shen |
| collection | DOAJ |
| description | To assess targeting of an epothilone folate conjugate (BMS-753493) to the folate receptor (FR)-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA) and LC–MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109) and FR– (M109) tumors. QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors) up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold). The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC–MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2–3-fold) whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor. |
| first_indexed | 2024-12-14T13:24:36Z |
| format | Article |
| id | doaj.art-ebd2251cedc4474c92e66080f6b9bb62 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 2211-3843 |
| language | English |
| last_indexed | 2024-12-14T13:24:36Z |
| publishDate | 2016-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-ebd2251cedc4474c92e66080f6b9bb622022-12-21T22:59:52ZengElsevierActa Pharmaceutica Sinica B2211-38352211-38432016-09-016546046710.1016/j.apsb.2016.07.009Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administrationHong Shen0Lifei Wang1Weiqi Chen2Krista Menard3Yang Hong4Yuan Tian5Samuel J. Bonacorsi6W. Griffith Humphreys7Francis Y. Lee8Jinping Gan9Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAPharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAPharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USADiscovery Oncology, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAChemistry, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAChemistry, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAChemistry, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAPharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USADiscovery Oncology, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USAPharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, USATo assess targeting of an epothilone folate conjugate (BMS-753493) to the folate receptor (FR)-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA) and LC–MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109) and FR– (M109) tumors. QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors) up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold). The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC–MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2–3-fold) whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor.http://www.sciencedirect.com/science/article/pii/S2211383516301058Folate receptorTumor selective targetingFolate receptor–expressing tumorEpothilone folate conjugateTissue distributionTumor uptake |
| spellingShingle | Hong Shen Lifei Wang Weiqi Chen Krista Menard Yang Hong Yuan Tian Samuel J. Bonacorsi W. Griffith Humphreys Francis Y. Lee Jinping Gan Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration Acta Pharmaceutica Sinica B Folate receptor Tumor selective targeting Folate receptor–expressing tumor Epothilone folate conjugate Tissue distribution Tumor uptake |
| title | Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration |
| title_full | Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration |
| title_fullStr | Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration |
| title_full_unstemmed | Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration |
| title_short | Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration |
| title_sort | tissue distribution and tumor uptake of folate receptor targeted epothilone folate conjugate bms 753493 in cd2f1 mice after systemic administration |
| topic | Folate receptor Tumor selective targeting Folate receptor–expressing tumor Epothilone folate conjugate Tissue distribution Tumor uptake |
| url | http://www.sciencedirect.com/science/article/pii/S2211383516301058 |
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