NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo
Mitsunori Harada,1 Caname Iwata,2 Hiroyuki Saito,1 Kenta Ishii,1 Tatsuyuki Hayashi,1 Masakazu Yashiro,3 Kosei Hirakawa,3 Kohei Miyazono,2 Yasuki Kato,1 Mitsunobu R Kano21Research Division, NanoCarrier Co, Ltd, Chiba, Japan; 2Department of Molecular Pathology, Graduate School of Medicine, University...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Dove Medical Press
2012
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/64ed1881f8b04f1087c864eb5a509d64 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:64ed1881f8b04f1087c864eb5a509d64 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:64ed1881f8b04f1087c864eb5a509d642021-12-02T00:36:58ZNC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo1176-91141178-2013https://doaj.org/article/64ed1881f8b04f1087c864eb5a509d642012-05-01T00:00:00Zhttp://www.dovepress.com/nc-6301-a-polymeric-micelle-rationally-optimized-for-effective-release-a10007https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Mitsunori Harada,1 Caname Iwata,2 Hiroyuki Saito,1 Kenta Ishii,1 Tatsuyuki Hayashi,1 Masakazu Yashiro,3 Kosei Hirakawa,3 Kohei Miyazono,2 Yasuki Kato,1 Mitsunobu R Kano21Research Division, NanoCarrier Co, Ltd, Chiba, Japan; 2Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 3Department of Surgical Oncology, Osaka City University, Osaka, JapanAbstract: Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors' own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity.Keywords: drug release, breast cancer, gastric cancerHarada MIwata CSaito HIshii KHayashi TYashiro MHirakawa KMiyazono KKato YKano MRDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 2713-2727 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine (General) R5-920 |
| spellingShingle |
Medicine (General) R5-920 Harada M Iwata C Saito H Ishii K Hayashi T Yashiro M Hirakawa K Miyazono K Kato Y Kano MR NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| description |
Mitsunori Harada,1 Caname Iwata,2 Hiroyuki Saito,1 Kenta Ishii,1 Tatsuyuki Hayashi,1 Masakazu Yashiro,3 Kosei Hirakawa,3 Kohei Miyazono,2 Yasuki Kato,1 Mitsunobu R Kano21Research Division, NanoCarrier Co, Ltd, Chiba, Japan; 2Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 3Department of Surgical Oncology, Osaka City University, Osaka, JapanAbstract: Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors' own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity.Keywords: drug release, breast cancer, gastric cancer |
| format |
article |
| author |
Harada M Iwata C Saito H Ishii K Hayashi T Yashiro M Hirakawa K Miyazono K Kato Y Kano MR |
| author_facet |
Harada M Iwata C Saito H Ishii K Hayashi T Yashiro M Hirakawa K Miyazono K Kato Y Kano MR |
| author_sort |
Harada M |
| title |
NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| title_short |
NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| title_full |
NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| title_fullStr |
NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| title_full_unstemmed |
NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| title_sort |
nc-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo |
| publisher |
Dove Medical Press |
| publishDate |
2012 |
| url |
https://doaj.org/article/64ed1881f8b04f1087c864eb5a509d64 |
| work_keys_str_mv |
AT haradam nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT iwatac nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT saitoh nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT ishiik nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT hayashit nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT yashirom nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT hirakawak nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT miyazonok nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT katoy nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo AT kanomr nc6301apolymericmicellerationallyoptimizedforeffectivereleaseofdocetaxelispotentbutislesstoxicthannativedocetaxelinvivo |
| _version_ |
1718403623275200512 |