Development of injectable thermosensitive polypeptide hydrogel as facile radioisotope and radiosensitizer hotspot for synergistic brachytherapy

Abstract

Brachytherapy is considered to be an unparalleled form of conformal radiation therapy, which involves the delivery of radiation directly to tumor lesions or the postoperative cavity. With the development of specific applicators, the exploitation of in situ drug-delivery platform introduces opportunities for the synchronous administration of radiosensitizers. In this study, an iodine-131 (I131)-labeled injectable thermosensitive methoxy poly(ethylene glycol)-b-poly(tyrosine) hydrogel (denoted as PETyr-I131) was developed via a facile method. The radioactive source of I131 was immobilized at the subcutaneous injection site and monitored via single-photon emission computed tomography in real time, and hematological and histopathological analyses revealed no obvious side effects. Additionally, the SmacN7 peptide conjugated with cell membrane-permeable oligosarginine (denoted as SmacN7-R9) was used to enhance the radiosensitivity of cancer cells, as confirmed by the results of reactive oxygen species detection, DNA damage assay, cell apoptosis assay, and clonogenic evaluation. Importantly, a synergistic brachytherapy treatment effect on tumor-bearing nude mice was achieved. The proposed thermosensitive supramolecular hydrogel platform, which conformally immobilizes radionuclides and delivers radiosensitizers by virtue of its proximity to the site of the primary tumor or the postoperative cavity, has great potential for achieving synergistic treatment outcomes with reduced radiation-related side effects. Statement of SignificanceIn this work, a kind of radioiodinated thermosensitive supramolecular hydrogel was developed, which was facilely used as the radioactive source for brachytherapy. Meanwhile, SmacN7-R9 peptide was combined as a model radiosensitizer to facilitate the activation of tumor cell apoptosis pathways and promotion of radiation-induced cytotoxicity. Synergistic brachytherapy outcomes were achieved from the in vitro and in vivo evaluations. Therefore, from the practical standpoint, this thermosensitive supramolecular hydrogel platform holds great potential for the 3D-conformally immobilizing radionuclide and delivering radiosensitizer by virtue of its proximity to the site of primary tumor lesions or postoperative cavity, resulting in synergetic treatment outcomes with reduced radiation associated side effects.