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Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.

ABSTRACT: Tumor-associated macrophages (TAMs) enhance tumor growth in mice and are correlated with a worse prognosis for breast cancer patients. While early therapies sought to deplete all macrophages, current therapeutics aim to reprogram pro-tumor macrophages (M2) and preserve those necessary for anti-tumor immune responses (M1). Recent studies have shown that c-MYC (MYC) is induced in M2 macrophages in vitro and in vivo where it regulates the expression of tumor-promoting genes. In a myeloid lineage MYC KO mouse model, MYC had important roles in macrophage maturation and function leading to reduced tumor growth. We therefore hypothesized that targeted delivery of a MYC inhibitor to established M2 TAMs could reduce polarization toward an M2 phenotype in breast cancer models. Methods: In this study, we developed a MYC inhibitor prodrug (MI3-PD) for encapsulation within perfluorocarbon nanoparticles, which can deliver drugs directly to the cytosol of the target cell through a phagocytosis independent mechanism. We have previously shown that M2-like TAMs express significant levels of the vitronectin receptor, integrin β3, and in vivo targeting and therapeutic potential was evaluated using αvβ3 integrin targeted rhodamine-labeled nanoparticles (NP) or integrin αvβ3-MI3-PD nanoparticles. Results: We observed that rhodamine, delivered by αvβ3-rhodamine NP, was incorporated into M2 tumor promoting macrophages through both phagocytosis-independent and dependent mechanisms, while NP uptake in tumor suppressing M1 macrophages was almost exclusively through phagocytosis. In a mouse model of breast cancer (4T1-GFP-FL), M2-like TAMs were significantly reduced with αvβ3-MI3-PD NP treatment. To validate this effect was independent of drug delivery to tumor cells and was specific to the MYC inhibitor, mice with integrin β3 knock out tumors (PyMT-Bo1 β3KO) were treated with αvβ3-NP or αvβ3-MI3-PD NP. M2 macrophages were significantly reduced with αvβ3-MI3-PD nanoparticle therapy but not αvβ3-NP treatment. Conclusion: These data suggest αvβ3-NP-mediated drug delivery of a c-MYC inhibitor can reduce protumor M2-like macrophages while preserving antitumor M1-like macrophages in breast cancer.

SUBMITTER: Esser AK

PROVIDER: S-EPMC7359087 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention.AimsThis review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs.Materials & methodsThe existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment.ResultsTAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies.DiscussionTAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs.ConclusionTAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

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Nanotherapy delivery of c-myc inhibitor targets Protumor Macrophages and preserves Antitumor Macrophages in Breast Cancer.

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