Active Nanoplateforms for PhotoDynamic Therapy – PDTX

Treatment of glioblastoma multiforme (GBM), a malignant tumor of the brain, is one of the most challenging problems. Surgery remains the basic treatment in which the bulk of the tumor is removed and the peripheral infiltrating part is the target of supplementary treatments. Despite advances in neurosurgery and radiotherapy the prognosis for patients with GBM, life expectancy at five years is not higher than 10%. Gliomas treatment by radiotherapy requires high accuracy in delivering ionizing radiation to reduce toxicity to surrounding tissues. Photodynamic therapy (PDT) offers a localized treatment approach in which improvements in local control of malignant cerebral gliomas may result in significant improved survival. Recent studies have been reported on the application of interstitial PDT for the treatment of brain tumors such as GBM. Nevertheless, light delivery remains a challenge issue. Only near infrared light in the range of 700-1100 nm can penetrate deep into the tissue because most tissue chromophores absorb weakly in the near infrared window. Unfortunately, most available photosensitizers have absorption bands at wavelengths shorter than 700 nm. Advances in nanobiotechnology have improved the prospects of delivery of therapeutics to GBM. Nanoparticles, as vectors, are able to overcome some of the problems experienced with conventional methods.
A novel approach to GBM treatment is suggested by the combination of radiotherapy and PDT, employing scintillating nanoparticles. Recent publications and our preliminary results lead us to suggest the development of nanoparticles for PDT, excited by radiotherapy (standard X-ray from an external corporal energy source) for the treatment of malignant cerebral gliomas. Our approach will consist in conjugating well adapted photosensitizer to the nanoscintillators based on gadolinium oxide compounds (Gd2O3:Tb3+, Gd2O3:Eu2+, Gd2O3:Eu3+Eu2+, Gd2O2S:Eu3+) which strongly absorb X-rays. When the nanoparticle-photosensitizer conjugates are targeted to the tumor tissue and stimulated by X-rays during radiotherapy, the particles generate light to activate the photosensitizer for PDT.
The project consists of four phases: (1) the synthesis of the core-shell nanoparticles, (2) the optimization and validation of the photosensitizer conjugation; (3) the Biotarget grafting (peptide grafting) to increase the selectivity of the nanoparticle for the cancer cell, and finally (4) the in-vitro and in-vivo biological evaluation for the validation of the strategy.
The innovation will involve the use of in vivo luminescent nanoparticles so that an external light source is not required to generate singlet oxygen (1O2) and support PDT. This new modality of PDT will offer the benefits of an improved radiation therapy at lower doses of irradiation. Consequently, the potential of damage to healthy cells will be reduced.
The advantages of this new PDT-radiation therapy using functionalized nanoparticles are: 1) two effective treatments (radiation therapy and PDT are combined; 2) the modality is efficient for deep cancer treatment; 3) the risk of radiation damage to healthy tissue is low. Therefore, the radiation and photodynamic therapies are combined and occur simultaneously. Anatomic MRI using the selected scintillating nanoparticles (because Gd is a good MRI contrast agent), will be used to precise the extension of the tumor tissue.