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

Abstract

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 Ac 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 ofAc (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 Ac, an effect which was more pronounced for theAc 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 Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing.

Uptake and subcellular distribution of radiolabeled polymersomes for radiotherapy

“…However, the analysis presented here could function as a prerequisite for the interpretation of 2-D experiments for comparison to 3-D in vitro systems, where radiation from neighbouring cells is much higher [21]. In addition, in current experimental set-up, the small amount of PMs translates to a small amount of alpha particles that are being emitted and a low delivered dose to cells.…”

“…225 Ac, for example, has multiple alpha emissions in its decay chain. The use of 225 Ac has seen therapeutic potential in glioma models [21]. For future studies, the use of 225 Ac might be more relevant to investigate the benefit of geographically fixing radiolabeled PMs intracellularly.…”

“…Although the uptake of other nano-carriers in cells has been documented, to our knowledge, no reports show the cellular and biological uptake mechanism of PMs. Recently, several reports show the use of PMs for TAT in both in vitro and in vivo experiments, suggesting that PMs can be used in a therapeutic setting [21,22]. The short range and high-LET of alpha particles requires prolonged localization close to the target cells, which can be reached if PMs are geographically fixed by cellular uptake.…”

Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma

“…A thorough understanding of the cellular distribution of the nanocarriers and interactions with cellular structures is a key issue in drug carrier systems due to the direct correlation that exists between cellular uptake, intracellular trafficking mechanism, and drug bioavailability, clinical efficacy, and therapeutic outcome of the entrapped therapeutic compound [17]. In a previous study, we reported on the kinetics of the uptake of fluorescently labeled polymersomes in U87 spheroids [16]. In about 4 days, the polymersomes have diffused nearly throughout the spheroids.…”

“…After 1 h incubation, the free FITC was removed by passing the solution through a PD10 column. For details regarding the polymersomes, see De Kruijff et al [16].…”