title: Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases.
abstract: Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tanei
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Fransisca
authors.initials: F
authors.lastname: Leonard
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Jenolyn F
authors.initials: JF
authors.lastname: Alexander
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas. KYokoi@houstonmethodist.org BGodin@houstonmethodist.org.
authors.forename: Biana
authors.initials: B
authors.lastname: Godin
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas. KYokoi@houstonmethodist.org BGodin@houstonmethodist.org.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokoi
mesh_terms: D000068196:Albumin-Bound Paclitaxel / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000188:drug therapy*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D009362:Neoplasm Metastasis
chemical_list: D000068196:Albumin-Bound Paclitaxel