Three talks on novel agents in MRI and cancer therapy

Manganese-enhanced MRI (MEMRI): Past and Future

Ichio Aoki

Manganese (Mn) has properties similar to those of Gadolinium (Gd) in terms of relaxivity. Manganese is a bioessential element and is found in many foods, with a median intake of 1.6–2.3 mg/day and an absorption rate of 5–10%, and homeostasis is maintained unless excessive intake is continued. Although it is difficult for Mn to exceed Gd in relaxivity because of its only five unpaired electrons (Gd has seven unpaired electrons), several Mn contrast agents with equivalent performance have been developed by designing chelates1. It is expected that Mn will be utilized as a "long half-life" metal complex contrast agent with higher safety and functionality in the future.
Experimentally, the use of Mn2+ as a Ca2+ analog, has been active since around 2000 under the term MEMRI2, and has been utilized as a neural depolarization marker3, a neuroaxonal tracer4, or a method of "staining" neural microstructures5 in vivo. Although the use of Mn as an ion produces some toxicity or physiological alterations depending on its dosage, it is an important contrast agent for basic biological studies that reflects cellular function. In this presentation, I would like to focus on Mn contrast agents and their properties, including (1) MEMRI for neuroscience, (2) Mn as a reactive contrast agent6, and (3) theranostic Mn contrast agents, which are both reactive and therapeutic7.

REFERENCES: [1] C. T. Farrar, et al., Radiology 2018, 287, 581-589. [2] A. C. Silva, et al., NMR Biomed 2004, 17, 532-543; G. Saar and A. P. Koretsky, Front Neural Circuits 2018, 12, 114. [3] Y. J. Lin and A. P. Koretsky, Magn Reson Med 1997, 38, 378-388. [4] R. G. Pautler, et al., Magn Reson Med 1998, 40, 740-748; K. S. Saleem, et al., Neuron 2002, 34, 685-700. [5] T. Watanabe, et al., NMR Biomed 2004, 17, 554-568; I. Aoki, et al., Neuroimage 2004, 22, 1046-1059; X. Yu, et al., Nat Neurosci 2005, 8, 961-968. [6] P. Mi, et al., Nat Nanotechnol 2016, 11, 724-730; J. Liu, et al., ACS Nano 2021, 15, 13526-13538. [7] I. Aoki, et al., Transl Res 2015; D. Kokuryo, et al., Nanomedicine 2015, 11, 229-238; E. Yuba, et al., Mol Pharm 2021, 18, 3342-3351.

Contrast agent-loaded self-folding macromolecular drug carrier for MRI in cancer diagnosis

Yutaka Miura

Nano-sized contrast agents (NCAs) have the potential to provide the highly specific contrast enhancement of tumors during MRI. Specifically, macromolecules bound to metal complexes can facilitate the increase in rotational correlation times, thereby enhancing molecular relaxivity. In this seminar, we’ll introduce our recent development of NCAs “a novel self-folding macromolecular drug carrier (SMDC)”1. The SMDC is formed by intramolecular self-folding of a single polymer chain containing well-arranged hydrophilic and hydrophobic segments in water. With this design, SMDC exhibit prolonged blood circulation with selective accumulation into solid tumors through enhanced permeability and retention effects, and the relaxivity value of SMDC was amplified with minimal loading of gadolinium complexes, resulting in highly clear tumor imaging.

(1) Advanced Science, 2304171, (2024) (DOI: 10.1002/advs.202304171).

Polymer design for cancer therapy and diagnosis

Kensuke Osada

Atoms make everything, meaning that if atoms are connected to prepare molecules, polymers, and assemblies over several hierarchies in right way, life emerges. Theoretically true, but it seems too challenging to reproduce this process using synthetic chemistry. However, it may be still possible to construct a structure that is hierarchically one level before life. With this hope in mind, we have designed primary structures of polymers and assemble them with DNA to produce a structure looked like virus. That structure produced proteins from the packaged DNA in cultured cells as well as cells in mice, and provoked therapeutic outcome in an intractable pancreatic cancer model mice by systemic application,1,2 demonstrating a virus function emerged in the nanoarchitectures constructed by synthetic polymers and DNA. In this talk, I would like to present a preparation of such nanoarchitectures for therapy and also diagnosis.

H. Cabral, K. Miyata, K. Osada, K. Kataoka, Block copolymer micelles in nanomedicine applications. Chemical Review 118 6844-6892 (2018)
T. A. Tockary, W. Foo, A. Dirisala, Q. Chen, S. Uchida, S. Osawa, Y. Mochida, X. Liu, H. Kinoh, H. Cabral, K. Osada, K. Kataoka, Single-stranded DNA-packaged polyplex micelle as AAV-inspired compact gene vector to systemically target stroma-rich pancreatic cancer. ACS Nano. 13 12732-12742 (2019)