PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted gallium porphyrin

Abstract

The development of novel theranostic agents is an important step in the pathway towards personalised medicine, with the combination of diagnostic and therapeutic modalities into a single treatment agent naturally lending itself to the optimisation and personalisation of treatment. In pursuit of the goal of a molecular theranostic suitable for use as a PET radiotracer and a photosensitiser for PDT, a novel radiolabelled peptide-porphyrin conjugate targeting the α6β1-integrin has been developed. (69/71)Ga and (68)Ga labelling of an azide-functionalised porphyrin has been carried out in excellent yields, with subsequent bioconjugation to an alkyne-functionalised peptide demonstrated. α6β1-integrin expression of two cell lines has been evaluated by flow cytometry, and therapeutic potential of the conjugate demonstrated. Evaluation of the phototoxicity of the porphyrin-peptide theranostic conjugate in comparison to an untargeted control porphyrin in vitro, demonstrated significantly enhanced activity for a cell line with higher α6β1-integrin expression when compared with a cell line exhibiting lower α6β1-integrin expression.

Fluorescent Imaging-Guided Chemotherapy-and-Photodynamic Dual Therapy with Nanoscale Porphyrin Metal-Organic Framework

“…Traditional methods (i.e., surgical resection, chemotherapy, and radiotherapy) still dominate cancer treatment but result in side effects and high recurrence rates . Multifunctional therapeutic platforms that combine new treatment modes, such as photothermal therapy (PTT) and photodynamic therapy (PDT), have all the advantages of a single therapy in improving efficiency with the added benefits of minimizing side effects, reducing drug dosage, and overcoming drug resistance . Imaging‐guided therapy systems (IGTSs) further integrate visualization technology to exert the combination of imaging and multitherapy .…”

Porphyrin–peptide conjugates in biomedical applications

“…A dodecapeptide (Table , entry 25), with good affinity for a different family of integrins (α 6 β 1 ) upregulated in multiple cancers, was recently used as targeting agent of a gallium(III) porphyrin, in pursuit of a cancer theranostic probe suitable as PET radiotracer and PS in PDT. The resulting conjugate proved to be selective and upon light irradiation cytotoxic on integrin over‐expressing cells, showing the possibility of using the same conjugate as both PDT and PET agent . This conjugate represents an improvement of the strategy previously reported by Mukai et al in which the conjugate between a tumor targeting peptide (a bombesin analogue, Table , entry 26) and a 64 Cu radiolabelled porphyrin was prepared as PET agent to evaluate in vivo the pharmacokinetics of the PS prior of the PDT treatment.…”

“…PDT requires high nanomolar to micromolar quantities of PS and its functionalization by cell‐penetrating peptides (CPP) has been shown to be effective in delivering a large amount of PS to the cell interior . Natural penetrating peptides and short oligoarginine sequences, inspired to protein transduction domains, have been conjugated to hydrophobic porphyrins and chlorins to enhance their uptake in cancer cells .…”

Current advances in ligand design for inorganic positron emission tomography tracers 68Ga, 64Cu, 89Zr and 44Sc

“…74 Boyle and co-workers used a similar chelate, TriMP, which was functionalised with an azide group to conjugate the porphyrin to a peptide. 75 Again, microwave irradiation was used to promote chelation of 68 Ga by the porphyrin, with complexation being completed within 7 minutes when heated to 110°C. 75 The polyfluorinated porphyrin, TFPP, was radiolabelled by Fazaeli and co-workers 76 the resulting complex showed high stability, with 99% remaining after 5 hours under physiological conditions.…”

“…75 Again, microwave irradiation was used to promote chelation of 68 Ga by the porphyrin, with complexation being completed within 7 minutes when heated to 110°C. 75 The polyfluorinated porphyrin, TFPP, was radiolabelled by Fazaeli and co-workers 76 the resulting complex showed high stability, with 99% remaining after 5 hours under physiological conditions. 76 However, heating at 100°C for 60 minutes was required for labelling of this system.…”