Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.

Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and...

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Autores principales:	Qingxin Mu, Jesse Yu, James I Griffin, Yan Wu, Linxi Zhu, Lisa A McConnachie, Rodney J Y Ho
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cb89d7d76ccd4535a410f364e5bbf9bc
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spelling	oai:doaj.org-article:cb89d7d76ccd4535a410f364e5bbf9bc2021-12-02T20:07:22ZNovel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.1932-620310.1371/journal.pone.0228557https://doaj.org/article/cb89d7d76ccd4535a410f364e5bbf9bc2020-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0228557https://doaj.org/toc/1932-6203Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.Qingxin MuJesse YuJames I GriffinYan WuLinxi ZhuLisa A McConnachieRodney J Y HoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 15, Iss 3, p e0228557 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qingxin Mu Jesse Yu James I Griffin Yan Wu Linxi Zhu Lisa A McConnachie Rodney J Y Ho Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
description	Early diagnosis along with new drugs targeted to cancer receptors and immunocheckpoints have improved breast cancer survival. However, full remission remains elusive for metastatic breast cancer due to dose-limiting toxicities of heavily used, highly potent drug combinations such as gemcitabine and paclitaxel. Therefore, novel strategies that lower the effective dose and improve safety margins could enhance the effect of these drug combinations. To this end, we developed and evaluated a novel drug combination of gemcitabine and paclitaxel (GT). Leveraging a simple and scalable drug-combination nanoparticle platform (DcNP), we successfully prepared an injectable GT combination in DcNP (GT DcNP). Compared to a Cremophor EL/ethanol assisted drug suspension in buffer (CrEL), GT DcNP exhibits about 56-fold and 8.6-fold increases in plasma drug exposure (area under the curve, AUC) and apparent half-life of gemcitabine respectively, and a 2.9-fold increase of AUC for paclitaxel. Using 4T1 as a syngeneic model for breast cancer metastasis, we found that a single GT (20/2 mg/kg) dose in DcNP nearly eliminated colonization in the lungs. This effect was not achievable by a CrEL drug combination at a 5-fold higher dose (i.e., 100/10 mg/kg GT). A dose-response study indicates that GT DcNP provided a therapeutic index of ~15.8. Collectively, these data suggest that GT DcNP could be effective against advancing metastatic breast cancer with a margin of safety. As the DcNP formulation is intentionally designed to be simple, scalable, and long-acting, it may be suitable for clinical development to find effective treatment against metastatic breast cancer.
format	article
author	Qingxin Mu Jesse Yu James I Griffin Yan Wu Linxi Zhu Lisa A McConnachie Rodney J Y Ho
author_facet	Qingxin Mu Jesse Yu James I Griffin Yan Wu Linxi Zhu Lisa A McConnachie Rodney J Y Ho
author_sort	Qingxin Mu
title	Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
title_short	Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
title_full	Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
title_fullStr	Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
title_full_unstemmed	Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
title_sort	novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.
publisher	Public Library of Science (PLoS)
publishDate	2020
url	https://doaj.org/article/cb89d7d76ccd4535a410f364e5bbf9bc
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Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis.

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