Design of a Targeting and Oxygen-Independent Platform to Improve Photodynamic Therapy: A Proof of Concept

Abstract

Photodynamic therapy (PDT) is a promising technique to treat different kinds of disease especially cancer. PDT requires three elements: molecular oxygen, a photo-activatable molecule called the photosensitizer (PS) and appropriate light. Under illumination, the PSs generate, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen, toxic, which then destroys the surrounding tissues. Even if PDT is used with success to treat actinic keratosis or prostate cancer for example, PDT suffers from two major drawbacks: the lack of selectivity of most of the PSs currently used clinically as well as the need for oxygen to be effective. To remedy the lack of selectivity, targeting the tumor neovessels is a promising approach to destroy the vascularization and cause asphyxia of the tumor. KDPPR peptide affinity for the NRP-1 receptor overexpressed on endothelial cells has already been proven. To compensate for the lack of oxygen, we focused on photoactivatable alkoxyamines, molecules capable of generating toxic radicals by light activation. In this paper we describe the synthesis of a multifunctional platform combining three units: a PS for an oxygen-dependent PDT, a peptide to target tumor neovessels and an alkoxyamine for an oxygen-independent activity. The synthesis of the compound was successfully carried out, the study of the photophysical properties showed that the PS retained its capacity to form singlet oxygen, the affinity tests confirmed the affinity of the compound for NRP-1. Thanks to the Electron Paramagnetic Resonance (EPR) spectroscopy, a technique of choice for radical investigation, the radicals generated by the illumination of the alkoxyamine could be detected. The proof of concept was thus successfully established.

Cascade strategy for triggered radical release by magnetic nanoparticles grafted with thermosensitive alkoxyamine

“…The alkoxyamine derivative carrying the coordinative phosphonic acid function on one hand and the nitroxyl moiety with thermosensitive C-ON bond on the other hand have been chosen here as a pool of radicals because: (i) the thermal lability of the C-ON bond of some alkoxyamines is well documented, [34][35][36][37] (ii) they can be covalently anchored to the IONP surface through the coordination of the phosphonate functionality, (iii) when attached to the magnetic nanoparticles surface, we expect that they will be activated under an ac field at lower reaction temperature since magnetic nanoparticles are able to create hot spots in their local environment, (iv) they may be used as radical source for biomedical applications since their high potential in the fight against tumors, parasites or bacteria through radicals release triggered by chemical, enzymatic, and physical (light excitation) events [38][39][40][41][42][43] has recently been demonstrated, [44][45][46] and the toxicity of non-activated alkoxyamines is low, (v) alkoxyamine may also be used as radical initiators for triggered and controlled polymerization in the systems where the simple heating is not possible. Note that to the best of our knowledge, the combination of thermosensitive alkoxyamines with magnetic nanoparticles activated by a magnetic field has never been reported up to date.…”

Recent Strategies to Develop Innovative Photosensitizers for Enhanced Photodynamic Therapy

“…In addition, the molecular design of novel PSs is also in great demand for clinical acceptance. In this section, to provide the reader with better insight into hypoxic tumor PDT, we summarized two main strategies to develop potential PSs, − including type I PSs (section ), potential PSs for synergistic cancer therapies (section ), enhanced intracellular O 2 concentration (section ), and fractional PDT (section ).…”

Sweetened Alkylated Verdazyls Effectively Kill Cancer Cells under Light Irradiation

“…Column chromatography was carried out using silica gel (100-200 mesh) and flash chromatography was performed on Reveleris X2 chromatographer using FlashPure Select Silica (15 μm). 1 H and 13 C NMR spectra were recorded on Bruker Advance III HD (400 MHz) at 400 and 101 MHz, respectively. 1 H NMR spectra were internally calibrated against residual undeuterated solvent peaks of DMSO (2.50 ppm), CHCl 3 (7.26 ppm) or CHD 2 OD (3.31 ppm); 13 C NMR spectra were internally calibrated against the solvent signals of DMSO-d 6 (39.5 ppm), CDCl 3 (77.0 ppm) or CD 3 OD (49.00 ppm).…”