Development of remotely controllable polymersomes for image guided drug-delivery deep within the body
The project aims the design, synthesis and evaluation of nanomaterials able responding to an external stimulus, such as a redox signal. Devices are developed essentially for biomedical applications in this project. The success of the project is conditioned to the development of efficient redox probes that are hydrolytically stable while may undergo rapid fragmentation in physiological solutes.
The project is based on a larger interdisciplinary network including organic chemists, polymer/material chemists, molecular biologists, radiologists, physics and medical experts. The overall goal of the project is to yield leads pertinent for human therapy. The program is structured around five interdisciplinary parts such as 1) Design, synthesis and characterization of X-ray sensitized probes; 2) Preparation of X-ray-optimized (“smart”) nanomaterials; 3) Radiolysis using conventional and non-conventional sources; toward holographic activations; 4) In vitro and in vivo imaging; Assessement of the biodistribution and the in vivo radiolysis; 5) Preparation of functionalized polymersomes for selective targeting.
Synthetic path has been found for the preparation of these nanomaterials. The materials were evaluated by standard physicochemical methods, and also under biological conditions.
The proposal describes the chemical part of a larger program initiated for the design and development of remotely controllable nanomaterials, and suggests the proof of principle for image guided in vivo drug delivery.
We consider this project as one having commercial potential. Results will be patented prior to publications/communications. Patenting appears possible after showing in vivo proof: we are working hard to meet the stake.
Medical applications in nanotechnology are a rapidly growing segment with significant impact on diagnosis and therapeutics for the treatment of human diseases. Nanoparticle (NP) based drug delivery is of particular interest as these materials may show prolonged circulation half-life, reduced non-specific uptake, and increased accumulation in specific tissues and organs through enhanced permeation and retention (EPR). Among the number of NP-based therapeutic approaches the delivery of an active compound by external trigger “on demand” and the intrinsic chemical and biochemical stimuli gated drug release are of particular interest. Nano-systems allowing “on demand” liberation are relying on stimuli responsive (also termed “smart”) materials triggered by pH, temperature modifications, variation of magnetic fields, or, light irradiation. Some of these methods can be applied in good spatio-temporal control, by which a high level of drug concentration (six- to ten fold) can be eventually attained. Although this strategy promises considerable advantages in term of reduced general toxicity and diminished resistance against the drug, the field is still in infancy: external activation of prodrugs with localized liberation of compounds stays a major challenge.
The project describes the chemical part of a larger program that aims the design, synthesis and study of remotely controllable polymersomes for biomedical applications and wish to finalize the development of a novel class of multisite device applicable in term in therapy, deep within the body. Polymersomes have proven their utility to deliver therapeutic agents to specific tissues/organs with potential therapeutic and theranostic applications where the therapeutic delivery can be simultaneously combined with diagnostic capabilities. They are extremely stable and robust - often too stable - for efficient drug delivery. The present application suggests method for image-guided local activation. The use of double selecting criteria, such as biological uptake and site selective activation would result in considerable reduction of adverse effects of many chemotherapy treatments what is always of paramount importance. In the heart of this novel activation methodology lies a recently developed fragmentation reaction that is based on (local) electron-transfer reaction triggered by penetrating X-ray, or, gamma light; the method was patented, and optimizations for biomedical applications are actively pursued. The method allows X-ray-gated delivery of virtually unrestricted variety of compounds having therapeutic interest in otherwise unaccessible (body) spaces, with the ability to follow the distribution and the liberation in real time by different bioimaging modalities, with the potential for multimodality. The project suggests to test a series of new redox fragmenting elements with charge-neutral nanoparticles (NPs) as sensitizers. Iron oxide NPs are considered which are among the few nanomaterials that are nontoxic, bio-compatibles, approved for therapeutic use and can be imaged. We believe, that the proposed system have the potential in theranostic applications combining thus both the ability to deliver a drug on a controlled manner and to monitor its distribution.
Although this application is limited to show the proof of principle of the concept, domains of potential biomedical applications can be foreseen, such as treatment of inflammation, drug abuse, where intracellular drug-delivery is needed and also in cancer therapy, minimizing the side effects of chemotherapy, and also where the major part of the required instrumentation is already implemented. Biomedical applications are only part of the potential field of interest, as the method may find application in microfabrication where 3D controlled manipulations in high spatial resolutions are needed in inaccessible spaces.
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (Laboratoire public)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
laboratoire d'optique appliquée
CNRS DR ILE DE FRANCE SUD
Unité de Technologies Chimiques et Biologiques pour la Santé UMR 8258
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
Laboratoire de Chimie des Polymères Organiques
Help of the ANR 580,052 euros
Beginning and duration of the scientific project: September 2014 - 36 Months