Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer

Yoo, Byunghee; Kavishwar, Amol; Wang, Ping; Ross, Alana; Pantazopoulos, Pamela; Dudley, Michael N.; Moore, Anna; Medarova, Zdravka

doi:10.1038/srep45060

Cited by 37 publications

(56 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthesis of the prototype nanodrugs have been previously described by us 6,29 and involved: (1) synthesis of dextran-coated magnetic nanoparticles 30 ; (2) conjugation of Cy5.5 fluorescent dye. The number of dyes per magnetic nanoparticle was determined as 3.2 (6); (3) conjugation of antisense LNA inhibiting oligonucleotides (ASO) or miRNA mimics through heterobifunctional linker N-succinimidyl 3-[2-pyridyldithio]-propionate (SPDP; Thermo Scientific Co., Rockford, IL) to produce MN-ASO or MN-miRNA [31][32][33] . ASO-scrambled (MN-ASOscr, single stranded) and mimics-scrambled (MN-miRNAscr, double stranded) nanodrugs were also synthesized as controls.…”

Section: Synthesis and Characterization Of Mir-216a Nanodrugsmentioning

confidence: 99%

See 1 more Smart Citation

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, βTC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulinproducing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.

show abstract

Section: Synthesis and Characterization Of Mir-216a Nanodrugsmentioning

confidence: 99%

“…ASO-scrambled (MN-ASOscr, single stranded) and mimics-scrambled (MN-miRNAscr, double stranded) nanodrugs were also synthesized as controls. The number of oligos per MN was determined as 4.0 using the electrophoresis analysis method described previously 33 .…”

Section: Synthesis and Characterization Of Mir-216a Nanodrugsmentioning

confidence: 99%

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our own studies, we identified miRNA-10b as a master regulator of the viability of metastatic tumor cells. We determined that miR-10b not only promotes the capacity of tumor cells to migrate and invade surrounding tissue (become metastatic) but also serves as a powerful master regulator of the viability of these cells ( 133 – 135 ). Detailed mechanistic studies confirmed the existence of a miR-10b-triggered pathway that regulates the viability and proliferation of tumor cells only after they have acquired the ability metastasize, pointing to miR-10b as a driver of resistance to anoikis ( 134 ).…”

Section: Examples Of Therapeutic Interventions That Fit the Paradigm mentioning

confidence: 99%

“…In a model of Stage IV metastatic breast cancer, we found that a weekly treatment protocol with MN-anti-miR-10b and low-dose doxorubicin demonstrated complete regression of pre-existing lung metastases in 65% of the animals and inhibition of multiple organ metastases in 94% of the animals. This translated into a significant reduction in cancer mortality in animals treated with MN-anti-miR10b and low-dose doxorubicin relative to control groups, including a group treated with monotherapy of standard dose doxorubicin, used to model standard-of-care ( 135 ).…”

Section: Examples Of Therapeutic Interventions That Fit the Paradigm mentioning

confidence: 99%

New Directions in the Study and Treatment of Metastatic Cancer

2018

Self Cite

View full text Add to dashboard Cite

Traditional cancer therapy has relied on a strictly cytotoxic approach that views non-metastatic and metastatic tumor cells as identical in terms of molecular biology and sensitivity to therapeutic intervention. Mounting evidence suggests that, in fact, non-metastatic and metastatic tumor cells differ in key characteristics that could explain the capacity of the metastatic cells to not only escape the primary organ but also to survive while in the circulation and to colonize a distant organ. Here, we lay out a framework for a new multi-pronged therapeutic approach. This approach involves modifying the local microenvironment of the primary tumor to inhibit the formation and release of metastatic cells; normalizing the microenvironment of the metastatic organ to limit the capacity of metastatic tumor cells to invade and colonize the organ; remediating the immune response to tumor neoantigens; and targeting metastatic tumor cells on a systemic level by restoring critical and unique aspects of the cell’s phenotype, such as anchorage dependence. Given the limited progress against metastatic cancer using traditional therapeutic strategies, the outlined paradigm could provide a more rational alternative to patients with metastatic cancer.

show abstract

“…In our own work, we have strived to incorporate imaging of drug delivery as an indispensable companion to drug development. We have extensively used dextran coated iron oxide nanoparticles as delivery vehicles for siRNA or antagomir therapeutics to tumors ( 26 – 31 ).…”

Section: Imagingmentioning

confidence: 99%

Guidelines for Rational Cancer Therapeutics

2017

Self Cite

View full text Add to dashboard Cite

Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

show abstract

Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer

Cited by 37 publications

References 14 publications

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

New Directions in the Study and Treatment of Metastatic Cancer

Guidelines for Rational Cancer Therapeutics

Contact Info

Product

Resources

About