Depletion of Mannose Receptor-Positive Tumor-Associated Macrophages via a Peptide-Targeted Star-Shaped Polyglutamate Inhibits Breast Cancer Progression in Mice

LEPLAND, ANNI; MALFANTI, ALESSIO; UKU HALJASORG; ASCIUTTO, ELIANA K.; MONICA PICKHOLZ; MAURO BRINGAS; SNEZANA DORDEVIC; LUIS SALUMAE; PART PETERSON; TEESALU, TAMBET; VICENT, MARIA J.; SCODELLER, PABLO

cancer research communications

american Association for Cancer Research

Año: 2022

2767-9764

Although many studies have explored the depletion of tumour-associated macrophages (TAMs) as a therapeutic strategy for solid tumours, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in a triple negative breast cancer (TNBC) mouse model. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In the TNBC model, a fluorescently labelled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumour lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (indicating immunomodulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent a novel design of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate.