Efficacy of Targeted ECO/miR-200c Nanoparticles for Modulating Tumor Microenvironment and Treating Triple Negative Breast Cancer as Non-invasively Monitored by MR Molecular Imaging

Schilb, Andrew; Ayat, Nadia; Vaidya, Amita; Hertz, Laura M; Hall, Ryan; Scheidt, Josef; Sun, Da; Sun, Zhanhu; Gopalakrishnan, Ramamurthy; Lü, Zheng Rong

doi:10.1007/s11095-021-03083-z

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…This effect is very likely mediated by hsa-miR-200c, regulating a number of other proliferation-associated proteins, most important Kras [ 23 , 60 ]. In the study of Schilb et al, where hsa-miR-200c was delivered via nanoparticles to MDA-MB 231 cells, a similar effect was observed [ 64 ]. In our experiments, DXR treatment reduced tumor growth in both groups (hsa-miR-200c positive and negative tumor cells).…”

Section: Discussionmentioning

confidence: 67%

Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification

Köhler

Dubovik

Hörterer

et al. 2022

Cancers

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Acquired drug resistance constitutes a serious obstacle to the successful therapy of cancer. In the process of therapy resistance, microRNAs can play important roles. In order to combat resistance formation and to improve the efficacy of chemotherapeutics, the mechanisms of the multifaceted hsa-miR−200c on drug resistance were elucidated. Upon knockout of hsa-miR−200c in breast carcinoma cells, a proteomic approach identified altered expression of glutathione S-transferases (GSTs) when cells were treated with the chemotherapeutic drug doxorubicin. In different hsa-miR−200c expression systems, such as knockout, inducible sponge and inducible overexpression, the differential expression of all members of the GST family was evaluated. Expression of hsa-miR−200c in cancer cells led to the repression of a multitude of these GSTs and as consequence, enhanced drug-induced tumor cell death which was evaluated for two chemotherapeutic drugs. Additionally, the influence of hsa-miR−200c on the glutathione pathway, which is part of the phase II detoxification mechanism, was investigated. Finally, the long-term effects of hsa-miR−200c on drug efficacy were studied in vitro and in vivo. Upon doxycycline induction of hsa-miR−200c, MDA-MB 231 xenograft mouse models revealed a strongly reduced tumor growth and an enhanced treatment response to doxorubicin. A combined treatment of these tumors with hsa-miR−200c and doxorubicin resulted in complete regression of the tumor in 60% of the animals. These results identify hsa-miR−200c as an important player regulating the cellular phase II detoxification, thus sensitizing cancer cells not expressing this microRNA to chemotherapeutics and reversing drug resistance through suppression of GSTs.

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Section: Discussionmentioning

confidence: 67%

Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification

Köhler

Dubovik

Hörterer

et al. 2022

Cancers

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“…The treatment of triple negative breast cancer cells and tumor models with targeted amino lipid RGD-PEG-ECO/miR-200c nanoparticles suppressed the expression of EMT markers, including ZEB1, FN, and EDB-FN, and significantly reduced the invasiveness of TNBC cancer cells and suppressed tumor proliferation in mouse models. MRMI with MT218 showed significantly smaller size and lower signal enhancement in the tumors treated with the RGD-PEG-ECO/miR-200c nanoparticles as compared to the control treated tumors, Figure . It also indicates that the miR-200c treatment has the potential to alter the TME of aggressive tumors.…”

Section: Mr Molecular Imaging Of Cancer With the Peptide Targeted Gbcamentioning

confidence: 92%

“…T 1 -weighted MR images of MDA-MB-231 triple negative breast cancer xenografts before (baseline) and 6 weeks after the treatment with RGD-PEG-ECO/siNS (nonspecific siRNA) and RGD-PEG-ECO/miR-200c nanoparticles in mice before and 20 min after injection of MT218 at 0.1 mmol/kg . The tumor locations are indicated by red circles.…”

Section: Mr Molecular Imaging Of Cancer With the Peptide Targeted Gbcamentioning

confidence: 99%

Targeted Contrast Agents for Magnetic Resonance Molecular Imaging of Cancer

Lü

Laney

2022

Acc. Chem. Res.

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Conspectus Magnetic resonance imaging (MRI) is a clinical imaging modality that provides high-resolution images of soft tissues, including cancerous lesions. Stable gadolinium(III) chelates have been used as contrast agents (CA) in MRI to enhance the contrast between the tissues of interest and surrounding tissues for accurate diagnostic imaging. Magnetic resonance molecular imaging (MRMI) of cancer requires targeted CA to specifically elucidate cancer-associated molecular processes and can provide high-resolution delineation and characterization of cancer for precision medicine. The main challenge for MRMI is the lack of sufficient sensitivity to detect the low concentration of the cellular oncogenic markers. In addition, targeted CA must satisfy regulatory safety requirements prior to clinical development. Up to now, there is no FDA-approved targeted CA for MRMI of cancer. In this Account, we discuss the latest developments in the design and development of clinically translatable targeted CA for MRMI of cancer, with an emphasis on our own research. The primary limitation of MRMI can be overcome by designing small molecular targeted CA to target abundant cancer-specific targets found in the tumor microenvironment (TME). For example, aggressive tumors have a unique extracellular matrix (ECM) composed of oncoproteins, which can be used as targetable markers for MRMI. We have designed and prepared small peptide conjugates of clinical contrast agents, including Gd-DTPA and Gd-DOTA, to target fibrin-fibronectin clots in tumors. These small molecular CA have been effective in enhancing MRMI detection of solid tumors and have demonstrated the ability to detect submillimeter cancer micrometastases in mouse tumor models, exceeding the detection limit of current clinical imaging modalities. We have also identified extradomain B fibronectin (EDB-FN), an oncofetal subtype of fibronectin, as a promising TME target to leverage in the design and development of small peptide targeted CA for clinical translation. The expression level of EDB-FN is correlated with invasiveness of cancer cells and poor patient survival of multiple cancer types. ZD2 peptide with a sequence of seven amino acids (TVRTSAD) was identified to specifically bind to the EDB protein fragment. Several ZD2 conjugates of macrocyclic GBCA, including Gd-DOTA and Gd(HP-DO3A), have been synthesized and tested in mouse tumor models. ZD2–N3-Gd(HP-DO3A) (MT218) with a high r1 relaxivity was selected as the lead agent for clinical translation. The physicochemical properties and preclinical assessments of MT218 are summarized in this Account. MRMI of EDB-FN with MT218 can effectively detect invasive tumors of multiple cancers with risk-stratification and monitor tumor response to anticancer therapies in mouse models. Currently, MT218 is in clinical trials for precision cancer MRMI. Herein, we will show that using targeted MRI contrast agents specific to abundant TME biomarkers is a pragmatic solution for effective precision cancer imaging in high spatial resolution. ...

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“…Overexpression of miR-150 in NK/T-cell lymphoma cells resulted in substantially enhanced sensitivity to ionizing radiation treatment [ 193 ], while miR-28-5p was found to suppress the growth of DLBCL cells by inhibiting the expression of YWHAZ protein [ 194 ]. In animal models, targeted delivery of miR-200c with nanoparticles suppressed proliferation of triple-negative breast cancer cells [ 195 ]. Up to recently published results, miR-15 and miR-16 mimics could be used for the therapy of Bcl-2-overexpressing tumors [ 45 ].…”

Section: Clinical Applications Of Mirnas Focusing On Hematological Ma...mentioning

confidence: 99%

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

Gaál

2022

IJMS

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MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are “micromanagers” of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.

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Efficacy of Targeted ECO/miR-200c Nanoparticles for Modulating Tumor Microenvironment and Treating Triple Negative Breast Cancer as Non-invasively Monitored by MR Molecular Imaging

Cited by 23 publications

References 35 publications

Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification

Combating Drug Resistance by Exploiting miRNA-200c-Controlled Phase II Detoxification

Targeted Contrast Agents for Magnetic Resonance Molecular Imaging of Cancer

Implication of microRNAs in Carcinogenesis with Emphasis on Hematological Malignancies and Clinical Translation

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