PCV - Programme interdiciplinaire en physique et chimie du vivant

Nanoparticules pour le Traitement Photodynamique Vasculaire des Tumeurs Cérébrales guidé par l'Imagerie – Nano-VTP

Submission summary

Photodynamic therapy (PDT) is being assessed as a therapy for the treatment of malignant gliomas. Despite conventional treatments, local relapses remain higher than 80%. PDT relies on the light activation of a photosensitizer (PS) localized in the tumor site. The treatment involves two steps. In the first one, the PS is injected to the patient, which will ideally be retained by neoplasic tissues. The second step aims at activating the PS by light irradiation ; in the presence of molecular oxygen, photooxidation reactions are induced, leading to the generation of cytotoxic reactive oxygen species and localized tumor eradication. If tumor destruction can result from direct cytotoxic damage, other indirect mechanisms seem to play a major part. One of them, the « anti-vascular effect », is characterized by the alteration of the tumor vascular network, that induces blood flow reduction, and in fine thrombi formation. A large and growing literature shows the essential role played by the anti-vascular effect in tumor eradication by PDT, which is then called Vascular Targeted Photodynamic therapy (VTP). This effect (and hence treatment efficacy) is potentiated by the enhanced and more selective accumulation of the PS in the tumor neovessels. A new PS conjugated to a peptide (ATWLPPR) targeting neuropilin-1 (NRP-1), a VEGF165 co-receptor, has been synthesized. This peptide binds to a recombinant chimeric form of the NRP-1 protein, as does the peptide-conjugated PS, but with a lower affinity. Intracellular uptake and photodynamic efficacy were improved in endothelial cells over-expressing NRP-1 due to the coupling of the PS to the peptide. In human malignant gliomas-bearing mice, the conjugated PS is taken up actively by tumor-associated endothelial cells, and induces, following treatment, a statistically significant tumor growth delay. Nevertheless, improvements can and need to be brought to our targeting strategy, in order to reduce non-specific phenomena arising from, on one hand, the hydrophobic character leading to the aggregation of the conjugate, which reduces its affinity for its target, and, on the other hand, from a large accumulation in the reticuloendothelial system, resulting in the degradation of the peptide. With the aim at overcoming these limitations, multifunctional furtive nanoparticles, decorated with a targeting peptide or pseudopeptide, can be used as vectors for the PS and can at the same time be detected by MRI. Other cyclic peptides, describing higher affinity, involved in the interaction with VEGF receptor 2 will be tested. Their small size (5–20 nm), along with original physical properties, make multifunctional hybrid nanoparticles patented, ideal tools for a combined action in diagnosis and therapy. The design of such multifunctional nanoparticles requires the elaboration of a composite structure : a core made of gadolinium sesquioxide, as a contrast agent for MRI, a peripheric hybrid shell bearing the targeting pseudopeptide, a hydrophilic polymer to limit hepatosplenic recognition, and, in the core, covalent grafting of the PS. Indeed, when functionalized with a peptidic ligand the nanoparticles could target NRP-1. The project consists of 5 phases : (1) the optimization and validation of the PS and pseudopeptides conjugations, (2) the study of the photophysical properties of the functionalized nanoparticles, (3) the determination of the molecular and cellular affinities, (4) the characterization of the metabolic profile and in vivo distribution and, (5) the comparison of the photodynamic efficacy on mice bearing orthotopic malignant gliomas. We will show that the biodistribution of the peptides-functionalized nanoparticles is favourable to a PS targeting strategy in the field of VTP, with a sufficient plasma circulating lifetime, a low non-specific hepatosplenic uptake and a fast elimination of non-captured nanoparticles. The principle of nanoparticles that can, at the same time, target angiogenic endothelial cells, allow imaging by MRI and lead to a treatment optimized (drug-light interval) of the targeted tumor is a novel concept. These nanoparticles for imaging and VTP of brain tumors encompass strong arguments necessary to an efficient therapeutic targeting : limiting the aggregation problem by transporting grafted PS molecules, preventing opsonins from adsorbing on the surface of nanoparticles and acting selectively by grafting on their periphery affin and stable peptides.

Project coordination

Muriel BARBERI-HEYOB (Université)

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.

Partner

Help of the ANR 441,570 euros
Beginning and duration of the scientific project: - 36 Months

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