Abstract

Regulating innate immunity is an emerging approach to improve cancer immunotherapy. Such regulation requires engaging myeloid cells by delivering immunomodulatory compounds to hematopoietic organs, including the spleen. Here we present a polymersome-based nanocarrier with splenic avidity and propensity for red pulp myeloid cell uptake. We characterized the in vivo behaviour of four chemically identical yet topologically different polymersomes by in vivo positron emission tomography imaging and innovative flow and mass cytometry techniques. Upon intravenous administration, relatively large and spherical polymersomes accumulated rapidly in the spleen and efficiently targeted myeloid cells in the splenic red pulp. When loaded with β-glucan, intravenously administered polymersomes significantly reduced tumour growth in a mouse melanoma model. We initiated our nanotherapeutic’s clinical translation with a biodistribution study in non-human primates, which revealed that the platform’s splenic avidity is preserved across species.

To systematically assess the effects of nanocarrier topology on biodistribution and immune cell affinity, authors established a small library of four polymersomes, namely SmS (ca. 100 nm diameter), SmT (ca. 200 × 80 nm length × width), LgS (ca. 500 nm diameter) and LgT (ca. 1 µm × 60 nm length × width).

Results from the nanoScan PET/CT

Authors evaluated polymersome biodistribution (Fig. 3a) and immune cell specificity (Fig. 3b) in C57BL/6 mice inoculated subcutaneously with B16F10 melanoma tumours in their left flanks. ⁸⁹Zr-polymersomes were administered in the animals’ left hind footpad to reach the lymphatics and lymph nodes near their tumours. In vivo PET/computed tomography (CT) imaging was performed two days after injection.

• SmS and SmT efficiently accumulated in the popliteal and iliac lymph nodes 
• LgS and LgT showed much lower accumulation in the popliteal and iliac lymph nodes
• In vivo PET imaging 48 h after intravenous injection revealed a drastically different polymersome biodistribution pattern compared with subcutaneous administration, with pronounced polymersome accumulation in the spleen, liver and bone marrow 

Fig. 3: Polymersome biodistribution and immune cell specificity in the B16F10 melanoma mouse model a,b, Schematic overview of ⁸⁹Zr-polymersome biodistribution studies by PET/CT imaging (a) and BODIPY-polymersome immune cell specificity studies by flow cytometry (b). c, Representative whole-body PET images taken 48 h after subcutaneous administration of ⁸⁹Zr-polymersomes via footpad injection. d, Biodistribution of subcutaneously administered ⁸⁹Zr-polymersomes, n = 4 per group. e, Uptake of subcutaneously administered BODIPY-polymersomes in specific immune cell types in the popliteal and iliac lymph nodes, n = 4 per group. f, Representative whole-body PET images taken 48 h after intravenous administration of ⁸⁹Zr-polymersomes via lateral tail vein injection. g, Biodistribution of intravenously administered ⁸⁹Zr-polymersomes, n = 4 per group. h, Uptake of intravenously administered BODIPY-polymersomes by immune cells in the spleen and bone marrow, n = 3 per group. Heatmaps of d and g show the average percentage injected dose per gram of tissue (%ID g⁻¹) of the ⁸⁹Zr-polymersomes per tissue as measured by ex vivo gamma counting.

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