Journal
CANCER RESEARCH COMMUNICATIONS
Volume 2, Issue 6, Pages 533-551Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2767-9764.CRC-22-0043
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Funding
- Estonian Research Council
- Feasibility fund of the University of Tartu [MOBTP185]
- European Regional De- velopment Fund
- Spanish Ministry of Science and Innovation [MOBTP185, PUT PSG38, 2014-2020.4.01.15-0012]
- Estonian government [PRG230]
- European Research Council [EAG79]
- Generalitat Valenciana
- FEDER funds (PO FEDER of Comunitat Valenciana 2014 - 2020) [ARENG51, RYC2020-028754-I]
- EsRC Mobilitas + grant
- UT EIK grant
- European Regional Development Fund [ERC-CoG-2014-648831]
- EuronanomedII project ECM-CART
- EuronanomedII project iNanoGun [ERC-PoC-2018-825798]
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This study developed a novel TAM-depleting agent and demonstrated its efficacy in a triple-negative breast cancer mouse model. The agent specifically targets CD206+ TAMs and does not show acute liver or kidney toxicity in vivo. Treatment with this agent showed potential benefits in reducing tumor progression and modulating the immune system. This research represents a novel design of a peptide-targeted nanotherapeutic for TAM depletion.
Although many studies have explored the depletion of tumor-associated macrophages (TAM) as a therapeutic strategy for solid tumors, 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 labeled 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 tumor 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.Significance: A peptide-targeted nanoformulation of DOX exclusively eliminates mannose receptor+ TAMs in breast cancer models, generating response without off-target effects (a drawback of many TAM-depleting agents under clinical study).
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