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.

Alpha-emitting radionuclides like actinium-225 (²²⁵Ac) are ideal candidates for the treatment of small metastasised tumours, where the long half-life of ²²⁵Ac enables it to also reach less accessible tumours. The main challenge lies in retaining the recoiled alpha-emitting daughter nuclides, which are decoupled from targeting agents upon emission of an alpha particle and can subsequently cause unwanted toxicity to healthy tissue. Polymersomes, vesicles composed of amphiphilic block copolymers, are capable of transporting (radio)pharmaceuticals to tumours, and are ideal candidates for the retention of these daughter nuclides. In this study, the Geant4 Monte Carlo simulation package was used to simulate ideal vesicle designs. Vesicles containing an InPO₄ nanoparticle in the core were found to have the highest recoil retention, and were subsequently synthesized in the lab. The recoil retention of two of the daughter nuclides, namely francium-221 (²²¹Fr) and bismuth-213 (²¹³Bi) was determined at different vesicle sizes. Recoil retention was found to have improved significantly, from 37 ± 4% and 22 ± 1% to 57 ± 5% and 40 ± 2% for ²²¹Fr and ²¹³Bi respectively for 100 nm polymersomes, as compared to earlier published results by Wang et al. where ²²⁵Ac was encapsulated using a hydrophilic chelate (Wang et al. 2014). To better understand the different parameters influencing daughter retention, simulation data was expanded to include vesicle polydispersity and nanoparticle position within the polymersome. The high retention of the recoiling daughters and the ²²⁵Ac itself makes this vesicle design very suitable for future in vivo verification.