Nathalie Schleich

Dual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging

We developed dual paclitaxel (PTX)/superparamagnetic iron oxide (SPIO)-loaded PLGA-based nanoparticles for a theranostic purpose. Nanoparticles presented a spherical morphology and a size of 240 nm. The PTX and iron loading were 1.84 ± 0.4 and 10.4 ± 1.93 mg/100 mg respectively. Relaxometry studies and phantom MRI demonstrated their efficacy as T₂ contrast agent. Significant cellular uptake by CT26 cells of nanoparticles was shown by Prussian blue staining and fluorescent microscopy. While SPIO did not show any toxicity in CT-26 cells, PTX-loaded nanoparticles had a cytotoxic activity. PTX-loaded nanoparticle (5 mg/kg) with or without co-encapulated SPIO induced in vivo a regrowth delay of CT26 tumors. Together these multifunctional nanoparticles may be considered as future nanomedicine for simultaneous molecular imaging, drug delivery and real-time monitoring of therapeutic response.

Comparison of active, passive and magnetic targeting to tumors of multifunctional paclitaxel/SPIO-loaded nanoparticles for tumor imaging and therapy

Multifunctional nanoparticles combining therapy and imaging have the potential to improve cancer treatment by allowing personalized therapy. Herein, we aimed to compare in vivo different strategies in terms of targeting capabilities: (1) passive targeting via the EPR effect, (2) active targeting of αvβ3 integrin via RGD grafting, (3) magnetic targeting via a magnet placed on the tumor and (4) the combination of magnetic targeting and active targeting of αvβ3 integrin. For a translational approach, PLGA-based nanoparticles loaded with paclitaxel and superparamagnetic iron oxides were used. Electron Spin Resonance spectroscopy and Magnetic Resonance Imaging (MRI) were used to both quantify and visualize the accumulation of multifunctional nanoparticles into the tumors. We demonstrate that compared to untargeted or single targeted nanoparticles, the combination of both active strategy and magnetic targeting drastically enhanced (i) nanoparticle accumulation into the tumor tissue with an 8-fold increase compared to passive targeting (1.12% and 0.135% of the injected dose, respectively), (ii) contrast in MRI (imaging purpose) and (iii) anti-cancer efficacy with a median survival time of 22 days compared to 13 for the passive targeting (therapeutic purpose). Double targeting of nanoparticles to tumors by different mechanisms could be a promising translational approach for the management of therapeutic treatment and personalized therapy.

Iron oxide-loaded nanotheranostics: Major obstacles to in vivo studies and clinical translation

A major issue in current cancer therapies is the lack of selectivity, which leads to damage in healthy tissues. Therefore, researchers have focused on numerous innovative targeting strategies to address this problem with the goal of increasing selectivity to avoid or minimize accumulation in healthy tissues. These strategies include (i) passive targeting, (ii) active targeting and (iii) stimuli-mediated targeting. Moreover, due to the high intra- and inter-variability found in tumors, nanotheranostics, which is the combination of a therapeutic and an imaging agent in a single vector, have emerged as indispensable tools for personalized therapy. Superparamagnetic iron oxide (SPIO) are MRI contrast agents that produce predominant T2 relaxation effects with excellent sensitivity compared with other MRI agents. Therefore, they have received increased interest in the field of theranostics during the past decade. However, few studies have been successfully conducted in vivo. This review aims to provide an overview of the targeted SPIO-based nanotheranostics recently used in pre-clinical studies and the major obstacles to in vivo studies and clinical translation. In the first section, we discuss personalized therapy as a biomedical application of theranostics. Then, we summarize the different imaging agents that have been used for theranostic purposes, with a focus on SPIO. In the third section, we detail recent advances in targeted SPIO-based nanotheranostics that have been used in pre-clinical studies. In the final sections, we discuss the limitations for in vivo studies, clinical translation and the clinical perspectives of SPIO-based nanotheranostics.

Paclitaxel-loaded micelles enhance transvascular permeability and retention of nanomedicines in tumors

Paclitaxel (PTX)-loaded polymeric micelles (M-PTX) have been shown to enhance the blood flow and oxygenation of tumors 24h after treatment. We hypothesized that these changes in the tumor microenvironment could lead to an enhancement of the EPR (enhanced permeability and retention) effect. M-PTX, administered 24h before analysis, increased the accumulation of macromolecules, nanoparticles and polymeric micelles in tumors. This increased EPR effect could be linked to normalization of the tumor vasculature and decreased interstitial fluid pressure. M-PTX used as a pre-treatment allowed a more effective delivery of three nanomedicines into tumors: polymeric micelles, liposomes and nanoparticles. These experiments demonstrate an enhanced EPR effect after M-PTX treatment, which lead to better availability and enhanced efficacy of a subsequent treatment with nanomedicines.

Chapter 6.2:Nanostructures Overcoming the Skin Barrier: Drug Delivery Strategies

The application of nanoparticles on the skin is an emerging field for topical delivery of active ingredients into the skin for dermatological and cosmetic applications as well as for transdermal drug delivery across the skin for systemic treatment.1–8 The review will focus on the use of nanocarriers...

Tumor Targeting by RGD-Grafted PLGA-Based Nanotheranostics Loaded with Paclitaxel and Superparamagnetic Iron Oxides

Theranostic nanoparticles have the potential to revolutionize cancer diagnosis and therapy. Many groups have demonstrated differential levels of tumor growth between tumors treated by targeted or untargeted nanoparticles; however, only few have shown in vivo efficacy in both therapeutic and diagnostic approach. Herein, we first develop and characterize dual-paclitaxel (PTX)/superparamagnetic iron oxide (SPIO)-loaded PLGA-based nanoparticles grafted with the RGD peptide, for a theranostic purpose. Second, we compare in vivo different strategies in terms of targeting capabilities: (1) passive targeting via the EPR effect, (2) active targeting of αvβ3 integrin via RGD grafting, (3) magnetic guidance via a magnet placed on the tumor, and (4) the combination of the magnetic guidance and the active targeting of αvβ3 integrin. In this chapter, we present the general flowchart applied for this project: (1) the polymer and SPIO synthesis, (2) the physicochemical characterization of the nanoparticles, (3) the magnetic properties of the nanoparticles, and (4) the in vivo evaluation of the nanoparticles for their therapeutic and diagnosis purposes. We employ the electron spin resonance spectroscopy and magnetic resonance imaging to both quantify and visualize the accumulation of theranostic nanoparticles into the tumors.