2017 – Nano-sized cytochrome p450 3a4 inhibitors to block hepatic – Paolini et al.

nano-pub — Fri, 01 Sep 2017 07:08:05 +0000

Authors

Marion Paolini1,2, Laurence Poul, PhD1, Céline Berjaud1, Matthieu Germain, PhD1, Audrey Darmon1, Maxime Bergère1, Agnès Pottier, PhD1, Laurent Levy, PhD1, Eric Vibert, MD, PhD2
1 – Nanobiotix SA, rue de Wattignies, Paris, France
2 – UMR-S 1193 INSERM/Paris-Sud University, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France

Summary

Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of biocompatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55).

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2017 – A new opportunity for nanomedicines – Paolini et al.

nano-pub — Wed, 14 Jun 2017 09:41:43 +0000

Authors

Marion Paolini1,2, Laurence Poul, PhD1, Audrey Darmon1, Matthieu Germain, PhD1, Agnès Pottier, PhD1, Laurent Levy, PhD1, Eric Vibert, MD, PhD2
1 – Nanobiotix SA, rue de Wattignies, Paris, France
2 – UMR-S 1193 Inserm/University Paris Sud, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France

Summary

Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application – to inhibit a drug’s metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6′,7′ dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24 h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel–micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man.

The post 2017 – A new opportunity for nanomedicines – Paolini et al. first appeared on Nano Publications.

Hepatocytes | Nano Publications

2017 – Nano-sized cytochrome p450 3a4 inhibitors to block hepatic – Paolini et al.

Authors

Summary

2017 – A new opportunity for nanomedicines – Paolini et al.

Authors

Summary