Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

Esser, Alison K.; Schmieder, Anne H.; Ross, Michael H.; Xiang, Jingyu; Su, Xinming; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Allen, John S.; Williams, Todd A.; Wickline, Samuel A.; Pan, Dipanjan; Lanza, Gregory M.; Weilbaecher, Katherine N.

doi:10.1016/j.nano.2015.10.003

Cited by 14 publications

(13 citation statements)

References 48 publications

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“…We have previously shown that αvβ3-NP bind to the tumor endothelium in vivo 54 . We next assessed the ability of αvβ3-rhodamine NP to bind myeloid cells in vivo .…”

Section: Resultsmentioning

confidence: 97%

“…However, the integrin αvβ3-targeting peptidomimetic binds with high affinity to the ligand-binding domain exposed with activated integrins, avoiding binding to inactivated αvβ3 integrin on quiescent cells. We have previously shown that integrin αvβ3-targeting to the neovasculature can be used to specifically deliver cargoes with αvβ3-PFC NP in pathologic animal models of cardiovascular, inflammatory disease and cancer 54 , 84 , 85 . The cMYC-MAX pathway is upregulated in tumor neovasculature, which also expresses the activated integrin 86 .…”

Section: Discussionmentioning

confidence: 99%

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

Esser¹,

Ross²,

Fontana³

et al. 2020

Theranostics

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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.

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“…We have previously shown that αvβ3-NP bind to the tumor endothelium in vivo 54 . We next assessed the ability of αvβ3-rhodamine NP to bind myeloid cells in vivo .…”

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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

Esser¹,

Ross²,

Fontana³

et al. 2020

Theranostics

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“…Fum-PD is ineffective when co-incubated with activated macrophages in culture, but it is effective against vascular tubule formation in vitro. 24, 57 Dxtl-PD can suppress macrophage inflammatory cytokine release in vitro and in vivo, as well as being anti-angiogenic 30 ( Supporting Information: S1 ). In the present study, α v β 3 -Dxtl-PD micelles, in addition to the anti-angiogenic anti-inflammatory effects elicited by targeting neoendothelial cells similar to α v β 3 -Fum-PD micelles, they likely bound phagocytic cells, possibly the M2 phenotype macrophages increased in antigen-induced asthma.…”

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

et al. 2017

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Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a clinically relevant rodent model.

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“…Thus, studies on bisphosphonates used alone or in combination with anticancer drugs or physicochemical methods for the treatment of tumorigenesis are promising fields of research, and highlight possibility of developing novel therapeutic strategies (70)(71)(72)(73)(74).…”

Section: Prospective Use Of Tams For Anticancer Therapymentioning

confidence: 99%

Tumor‑associated macrophages: Role in the pathological process of tumorigenesis and prospective therapeutic use (Review)

et al. 2020

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The aim of the present study was to evaluate the current body of knowledge regarding tumor-associated macrophages (TAMs) and their potential use in antitumor therapy, based on their role in the pathological process of tumorigenesis. For this purpose, a critical analysis of published data and summarization of the findings available from original studies, focusing on the role of TAMs in the pathological process, and their potential therapeutic application was performed. Promising key avenues of research were identified in this field. The following issues seem the most promising and thus worth further investigation: i) The process of M1/M2 macrophage polarization, macrophage characteristics at intermediate polarization steps and their role in the tumor process; ii) determining the conditions necessary for transitions between the M1 and M2 macrophage phenotypes and the role of signals from the microenvironment in this process; iii) cause-and-effect associations between the quantity and quality of macrophages, and the prognosis and outcome of the pathological process; iv) modulation of macrophages and stimulation of their phagocytic activity with drugs; v) targeted vector-based systems for drug delivery to macrophages; and vi) targeted drug delivery systems with macrophages as carriers, thus potentially combining chemotherapy and immunotherapy.

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Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

Cited by 14 publications

References 48 publications

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

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

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

Tumor‑associated macrophages: Role in the pathological process of tumorigenesis and prospective therapeutic use (Review)

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