Molecular Theranostic Agents for Photodynamic Therapy (PDT) and Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool that can provide important insights for medical treatment monitoring and optimization. Photodynamic therapy (PDT), a minimally invasive treatment for various types of tumors, is drawing increasing interest thanks to its temporal and spatial selectivity. The combination of MRI and PDT offers real-time monitoring of treatment and can give significant information for drug-uptake and light-delivery parameters optimization. In this review we will give an overview of molecular theranostic agents that have been designed for their potential application in MRI and PDT.

2 for two-photon absorption) increases the production of cytotoxic species and enhances the 45 treatment efficacy. New PSs are designed and studied in order to respond to these criteria. Two near infrared, have recently been designed. Padeliporfin (Tookad ® WST11), with an excitation 48 wavelength at 763 nm ( = 100 000 M -1 cm -1 ), has been approved for the treatment of prostate 49 cancer.
[12] Redaporfin (LUZ11), that can be activated at 749 nm ( = 140 000 M -1 cm -1 ) has been 50 approved for biliary tract cancer and is also moving to other clinical trials. [13,14]  [18] It has already proven to be powerful for therapy monitoring in oncology and for drug 66 development. [19] The MR signal contrast arises from the differences of proton properties such as the 67 relaxation times (T1 and T2) or the density of water molecules.
[20] These properties are acquired 68 using appropriate MR pulse sequences; they highlight different proton behaviors and allow tissue 69 discrimination. In some cases, the contrast between healthy and diseased tissue is weak and the use 70 of a contrast agent is necessary. Clinically used contrast agents are small gadolinium-based 71 complexes containing octadentate chelators based on macrocyclic (GdDOTA with DOTA = 72 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) or linear (GdDTPA with DTPA = 73 diethylenetriamine pentaacetate) structures (Scheme 2). The efficiency of a contrast agent is 74 measured by its relaxivity that corresponds to the ability to decrease the relaxation time T1 of water 75 protons in presence of a paramagnetic gadolinium complex at a concentration of 1 mM.

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The PDT-induced changes in the tumoral area alter the proton behaviors and these changes can 77 also be strongly emphasized by the presence of a contrast agent. The image modification can thus 78 bring essential informations to estimate the PDT effect. It is then possible to establish relations 79 between this effect and the drug and light parameters. The latters can then be finely tuned in order 80 to increase the efficiency of the treatment. [21] assessment of tumor response to PDT. [24][25][26] Informations obtained shortly after treatment could 89 also be obtained. [25] 90 The optimization of the PDT treatment can be further improved using theranostic agents. With 91 this approach, both the imaging and the therapeutic agents will have the same biodistribution and 92 bioelimination behaviors. Gadolinium-based contrast agents linked to a porphyrin-based PS are 93 expected to confer increased tumoral residence time, thus they provide a longer time window to 94 monitor the treatment. They also have increased relaxivities compared to classical MRI contrast 95 agents. Therefore, they can be administered at much lower dose than current clinical contrast agents 96 and offer enhanced safety. The nanoparticle approaches for MRI and PDT applications have 97 attracted increasing attention during the past decade. [5][6][7]27] In spite of the efficient targeting and 98 high payload of some nanotheranostic agents, clinical translation has not yet been possible. [6,7,27] 99 Molecular theranostic agents for PDT and MRI have been developed to a lesser extent; however, 100 interesting results have been obtained. These small or medium-size molecular agents have their own 101 strengths and advantages (such as high reproducibility, stability, purity and good biocompatibility) 102 and this approach continues to draw attention for cancer treatment. [28] Several porphyrin analogues have been associated to Gd(III) complexes, their ability to 105 accumulate in cancer cells and/or their relaxivity have been considered without exploring their 106 potential as PDT PS. At an early stage, two compounds, gadophrin-2 and gadophrin-3, composed 107 respectively of a free-base and a copper(II) porphyrin linked to two GdDTPA complexes have been 108 investigated. Studies in mice have shown comparable pharmacological properties and these PSs substantial image contrast enhancement of the tumor compared to adjacent normal tissue in 124 tumor-bearing mice evidenced the affinity of the compound for tumor tissue. The photoinduced commercial HPD PS. This porphyrin-Gd complex conjugate was the first prototype built for MRI 128 and PDT.

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More than a decade later, Pandey and collaborators extensively investigated several theranostic 131 agents that combine diagnostic imaging (MR and fluorescence imaging) and PDT treatment 132 properties. They are based on different photosensitizers (pyropheophorbide analogues with 133 different lipophilic/hydrophilic chains) linked to one, two, three or six GdDTPA complexes. [39][40][41][42] 134 In these compounds, the linkage is realized through the C-functionalization of the

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In order to obtain contrast agents with high relaxivity at high magnetic fields, the strategy of

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The theranostic agents reported so far are activated by one-photon absorption, with excitation 251 wavelengths below 700 nm. The two-photon excitation process allows to use excitation wavelengths treatment precision can be obtained but the application to bulky tumors is currently limited. The

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The design and study of molecular theranostic agents for potential applications in MR imaging 297 and PDT treatment has been highlighted and discussed.

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Compared to small commercial contrast agents, the MR imaging properties of these theranostic