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Synthesis and Validation of a Bioinspired Catechol-Functionalized Pt(IV) Prodrug for Preclinical Intranasal Glioblastoma Treatment.

ABSTRACT: Glioblastoma is the most malignant and frequently occurring type of brain tumors in adults. Its treatment has been greatly hampered by the difficulty to achieve effective therapeutic concentration in the tumor sites due to its location and the blood-brain barrier. Intranasal administration has emerged as an alternative for drug delivery into the brain though mucopenetration, and rapid mucociliary clearance still remains an issue to be solved before its implementation. To address these issues, based on the intriguing properties of proteins secreted by mussels, polyphenol and catechol functionalization has already been used to promote mucopenetration, intranasal delivery and transport across the blood-brain barrier. Thus, herein we report the synthesis and study of complex 1, a Pt(IV) prodrug functionalized with catecholic moieties. This complex considerably augmented solubility in contrast to cisplatin and showed a comparable cytotoxic effect on cisplatin in HeLa, 1Br3G and GL261 cells. Furthermore, preclinical in vivo therapy using the intranasal administration route suggested that it can reach the brain and inhibit the growth of orthotopic GL261 glioblastoma. These results open new opportunities for catechol-bearing anticancer prodrugs in the treatment for brain tumors via intranasal administration.

SUBMITTER: Mao X

PROVIDER: S-EPMC8774041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles.

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| S-EPMC2582270 | biostudies-other

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| S-EPMC5471451 | biostudies-literature

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| S-EPMC2536766 | biostudies-literature

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| S-EPMC4916484 | biostudies-literature

?(V)?(3) integrin-targeted PLGA-PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug.

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| S-EPMC3358506 | biostudies-literature

Facile Synthesis of a Pt(IV) Prodrug of Cisplatin and Its Intrinsically <sup>195m</sup>Pt Labeled Analog: A Step Closer to Cancer Theranostic.

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| S-EPMC6321036 | biostudies-literature

Photoinduced reduction of Pt(IV) within an anti-proliferative Pt(IV)-texaphyrin conjugate.

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| S-EPMC4241752 | biostudies-literature

Improvements in the Synthesis and Understanding of the Iodo-bridged Intermediate en Route to the Pt(IV) Prodrug Satraplatin.

Project description:Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3.

| S-EPMC4243179 | biostudies-literature

Synthesis and characterization of Pt(IV) fluorescein conjugates to investigate Pt(IV) intracellular transformations.

Project description:Pt(IV) anticancer compounds typically operate as prodrugs that are reduced in the hypoxic environment of cancer cells, losing two axial ligands in the process to generate active Pt(II) species. Here we report the synthesis of two fluorescent Pt(IV) prodrugs of cisplatin in order to image and evaluate the Pt(IV) reduction process in simulated and real biological environments. Treatment of the complexes dissolved in PBS buffer with reducing agents typically encountered in cells, glutathione or ascorbate, afforded a 3- to 5-fold fluorescence turn-on owing to reduction and loss of their fluorescein-based axial ligands, which are quenched when bound to platinum. Both Pt(IV) conjugates displayed moderate cytotoxicity against human cancer cell lines, with IC50 values higher than that of cisplatin. Immunoblotting and DNA flow cytometry analyses of one of the complexes, Pt(IV)FL2, revealed that it damages DNA, causes cell cycle arrest in S or G2/M depending on exposure time, and ultimately triggers apoptotic cell death. Fluorescence microscopic studies prove that Pt(IV)FL2 enters cells intact and undergoes reduction intracellularly. The results are best interpreted in terms of a model in which the axial fluorescein ligands are expelled through lysosomes, with the platinum(II) moiety generated in the process binding to genomic DNA, which results in cell death.

| S-EPMC3800427 | biostudies-literature

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