Project

REFINE Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices

Goal: The REFINE Project website: www.refine-nanomed.eu
Interact with the REFINE Project: https://www.researchgate.net/post/The_REFINE_Project_asks_you

REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medical products and medical devices that are based on nanomedicines and biomaterials. We will demonstrate the relevance of the framework for the most pressing regulatory challenges, which are: borderline products, nanosimilars, and products combining several functionalities. We will identify the regulatory challenges with Regulation Authorities from Europe and abroad, and design methods for tiered decision tree, guided by the latest scientific knowledge.  We will study/predict physiological distribution of nanomedicines and biomaterials, as well as develop and validate new analytical or experimental methods and assays requested by the regulators.  These latter development will be performed in a quality management system, ensuring the possible standardisation of our assays.

Date: 1 December 2017 - 28 February 2022

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Adriele Prina-Mello
added 4 research items
Docetaxel (DTX) is an anticancer treatment widely used in the clinic for the treatment of various human malignancies, including Non-Small-Cell Lung Cancer (NSCLC). Its low water solubility and systemic toxicity, however, negatively impact the clinical application of such drug. In order to improve DTX solubility in biological fluids and decrease its adverse effects in patients, the scientific community is currently focusing on developing drug delivery systems where DTX is the payload. In this context, the present study aims at presenting a step forward in the development of platforms based on gold complexes for multifunctional approaches (theragnostic tools) and stimuli-responsive therapies. Tetrachloroauric acid (HAuCl4) were complexed with the antitumor drug and dicarboxylic acid-terminated polyethylene-glycol (PEG) to form the nanometric complex named DTX-Au-PEG. Following reduction with sodium borohydride (NaBH4), the DTX-Au-PEG complex formed hybrid-metal nanoparticles (DTX IN PEG-AuNPs), where DTX was protected in the gold core embedded within the polymer chains. To achieve therapeutic targeting, DTX-Au-PEG complex and DTX IN PEG-AuNPs were chemical combined with the human anti-EGFR polyclonal antibody, which recognizes the hERG1 channel aberrantly expressed on the membrane of human lung cancer cells. The active targeting was demonstrated by various analytical techniques (Raman and UV–vis spectroscopies); whereas, in vitro experiments on tissue-mimetic, three-dimensional (3D) tumoroids grown at the Air-Liquid Interface (ALI) demonstrated that DTX encapsulation within a gold core strongly influenced the drug efficacy, with a significant increase of the DTX therapeutic index when AuNPs were specifically targeted against EGFR. Collectively, our study demonstrated that a drug delivery system based on Au (III)-DTX complexes constitutes an encouraging chemical approach to build Au (III) complexes into real chemotherapeutic drugs for cancer treatment.
Hypothesis The implementation of the proposal from the European Chemical Agency (ECHA) to restrict the use of nanoplastics (NP) and microplastics (MP) in consumer products will require reliable methods to perform size and mass-based concentration measurements. Analytical challenges arise at the nanometre to micrometre interface, e.g., 800 nm–10 µm, where techniques applicable at the nanometre scale reach their upper limit of applicability and approaches applicable at the micrometre scale must be pushed to their lower limits of detection. Experiments Herein, we compared the performances of nine analytical techniques by measuring the particle size distribution and mass-based concentration of polystyrene mixtures containing both nano and microparticles, with the educational aim to underline applicability and limitations of each technique. Findings Light scattering-based measurements do not have the resolution to distinguish multiple populations in polydisperse samples. Nanoparticle tracking analysis (NTA), nano-flowcytometry (nFCM) and asymmetric flow field flow fractionation hyphenated with multiangle light scattering (AF4-MALS) cannot measure particles in the micrometre range. Static light scattering (SLS) is not able to accurately detect particles below 200 nm, and similarly to transmission electron microscopy (TEM) and flow cytometry (FCM), is not suitable for accurate mass-based concentration measurements. Alternatives for high-resolution sizing and concentration measurements in the size range between 60 nm and 5 µm are tunable resistive pulse sensing (TRPS) and centrifugal liquid sedimentation (CLS), that can bridge the gap between the nanometre and micrometre range.
Although interest and funding in nanotechnology for oncological applications is thriving, translating these novel therapeutics through the earliest stages of preclinical assessment remains challenging. Upon intravenous administra-tion, nanomaterials interact with constituents of the blood inducing a wide range of associated immunotoxic effects. The literature on the immunological interactions of nanomaterials is vast and complicated. A small change in a particular characteristic of a nanomaterial (e.g., size, shape, or charge) can have a significant effect on its immunological profile in vivo, and poor selection of specific assays for establishing these undesirable effects can overlook this issue until the latest stages of preclinical assessment. This work describes the current literature on unintentional immunological effects associated with promising cancer nanomaterials (liposomes, dendrimers, mesoporous silica, iron oxide, gold, and quantum dots) and puts focus on what is missing in current preclinical evaluations. Opportunities for avoiding or limiting immunotoxicity through efficient preclinical assessment are discussed, with an emphasis placed on current regulatory views and require-ments. Careful consideration of these issues will ensure a more efficient preclinical assessment of cancer nanomedicines, enabling a smoother clinical translation with less failures in the future.
Adriele Prina-Mello
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Adriele Prina-Mello
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The REFINE Project website: www.refine-nanomed.eu
REFINE proposes a Regulatory Science Framework for the risk-benefit assessment of medical products and medical devices that are based on nanomedicines and biomaterials. We will demonstrate the relevance of the framework for the most pressing regulatory challenges, which are: borderline products, nanosimilars, and products combining several functionalities. We will identify the regulatory challenges with Regulation Authorities from Europe and abroad, and design methods for tiered decision tree, guided by the latest scientific knowledge.  We will study/predict physiological distribution of nanomedicines and biomaterials, as well as develop and validate new analytical or experimental methods and assays requested by the regulators.  These latter development will be performed in a quality management system, ensuring the possible standardisation of our assays.