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).

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.

Summary

Congress: CLINAM, 23rd May 2011

Contents: The development of new activatable drug nanocarriers, with multiple functionalities, presents a promising approach for cancer treatment.

Improved drug delivery and controlled drug release at the tumor site may have considerable benefit by increasing treatment efficacy while reducing side effects and toxicity. Further, the possibility to monitor both nanocarrier accumulation and drug release via current clinical imaging techniques may be particularly relevant for an optimal treatment.

Within the European project “Sonodrugs”, we investigated the opportunity of triggering the drug release from new nanocarriers (temperature and pressure-sensitive) thanks to High Intensity Focused Ultrasounds (HIFU) and monitoring the release profile of the drug at the tumor site thanks to Magnetic Resonance Imaging (MRI) imaging.

A new versatile thermosensitive liposome has been designed and developed to efficiently encapsulate a drug (doxorubicin) and a contrast agent (superparamagnetic iron oxide nanoparticles).

Summary

Photodynamic therapy in the elderly and heavily pretreated cancer patient populations may represent a promising therapeutical option in the management of malignant diseases provided that different approaches bring real improvement for its clinical application.

Silica-based nanocarrier encapsulating photosensitizers, the protoporphyrin IX (Pp IX), have been designed to improve the tumor bioavailability, to reduce photosensitizer accumulation in the skin and to differentially deliver the nanocarriers to cell organelles.

Pp IX silica-based nanocarriers were explored in in vitro and in vivo models with the ambition to improve knowledge on the role of biological factors in the photodamages. Some key features are presented here.

Summary

A new versatile hybrid nano carrier has been designed using a “soft chemistry” synthesis, to efficiently encapsulate a photosensitizer – the protoporphyrin IX (Pp IX) – while preserving its activity intact in biological environment for advantageous use in photodynamic therapy (PDT). […]