The therapeutic potential of polymersomes loaded with 225Ac evaluated in 2D and 3D in vitro glioma models

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Abstract

Graphical abstract

Alpha-emitting radionuclides like 225Ac have great potential in tumour therapy due to their high linear energy transfer (LET). In this study, polymersomes have been used to retain recoiling daughter atoms to allow for safe tumour targeting, and their in vitro characteristics have been studied in U87 spheroidal tumours. Tumour growth inhibition or destruction when challenged with small amounts of 225Ac-containing polymersomes shows their great therapeutic potential.

Alpha emitters have great potential in targeted tumour therapy, especially in destroying micrometastases, due to their high linear energy transfer (LET). To prevent toxicity caused by recoiled daughter atoms in healthy tissue, alpha emitters like 225Ac can be encapsulated in polymeric nanocarriers (polymersomes), which are capable of retaining the daughter atoms to a large degree. In the translation to a (pre-)clinical setting, it is essential to evaluate their therapeutic potential. As multicellular tumour spheroids mimic a tumour microenvironment more closely than a two-dimensional cellular monolayer, this study has focussed on the interaction of the polymersomes with U87 human glioma spheroids. We have found that polymersomes distribute themselves throughout the spheroid after 4 days which, considering the long half-life of 225Ac (9.9 d) (Vaidyanathan and Zalutsky, 1996), allows for irradiation of the entire spheroid. A decrease in spheroidal growth has been observed upon the addition of only 0.1 kBq 225Ac, an effect which was more pronounced for the 225Ac in polymersomes than when only coupled to DTPA. At higher activities (5 kBq), the spheroids have been found to be destroyed completely after two days. We have thus demonstrated that 225Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing.

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