News & Analysis
News & Analysis
Highlighting the latest news and research in therapeutic delivery
miRNAs responsible for inhibiting angiogenesis in cancer
Contents
Family of miRNAs reported to prevent angiogenesis by inhibiting the action of cancer cytokines
A collaboration between scientists from the University of Texas (TX, USA) and the Karmanos Cancer Institute in Michigan (MI, USA), has elucidated the mechanism by which miR-200, a miRNA family, inhibits the epithelial-mesenchymal transition (EMT) in cancer. The team demonstrated that miR-200 inhibits angiogenesis by specifically targeting the chemokines IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1), two key molecules in tumor formation secreted by tumor endothelial and cancer cells. The group, led by Anil Sood, Professor of Gynecology, analyzed ovarian, renal, breast and non-small-cell lung cancer samples for expression of miR-200 family members. They found better survival rates for patients with lung, ovarian, kidney or triple-negative breast cancers who have high levels of miR-200 expression.
“The team used nanoparticles ... to deliver miR-200 into the tumor endothelium in mouse models of lung and triple-negative breast cancers. They observed reductions in primary tumor size and volume, and angiogenesis compared with untreated controls...”
CXCL1, and identified binding sites for miR200 on these genes. Data-mining studies in public miRNA and messenger RNA databases demonstrated a correlation of high IL-8 levels with poor survival rates, and low miR-200 levels with high IL-8 levels in lung, ovarian, kidney and triple-negative breast cancer. Interestingly, the team found elevated expression of IL-8 and CXCL1 in these cancer types compared with hormone-positive breast cancers. “We feel that these results are significant since they help to explain the divergent findings with regard to the miR-200 family in various cancer types,” commented Sood. miRNAs act by regulating gene expression. Until now it has been known that miR-200 inhibits EMT, a cellular transition associated with cancer progression and metastasis. During EMT, cells lose adhesion and increase motility by reduced expression of the adhesion molecule E-cadherin. This study shows for the first time a direct implication of miR-200 in angiogenesis. “There are several potential implications moving forward,” added Sood. “First, this work identifies cancer types (e.g., ovarian, renal, lung) where miR-200 could have therapeutic benefit. Second, conversely, it identifies cancer types where miR-200 would be unlikely to have therapeutic benefit (e.g., luminal breast cancer). Third, this work identified key downstream pathways affected by miR-200 related to angiogenesis and as such could be useful for biomarkers in monitoring therapeutic response.” Future studies will focus on exploring this and other miRNA pathways and their therapeutic potential, including testing the utility of miR-200 along with chemotherapy drugs.
The team used nanoparticles, previously developed in collaboration with Gabriel Lopez, Professor in the Department of Experimental Therapeutics at The University of Texas, to deliver miR-200 into the tumor endothelium in mouse models of lung and triple-negative breast cancers. They observed reductions in primary tumor size and volume, and angiogenesis compared with untreated controls, as well as sharp reductions in IL-8 levels and angiogenesis in ovarian cancer models. Delivering miR-200 directly to blood vessels by way of chitosan nanoparticles resulted in a 92% reduction in ovarian cancer metastases compared with controls. Studies in cell lines confirmed the effect of miR-200 in decreasing levels of IL-8 and
Source: Pecot CV, Rupaimoole R, Yang D et al. Tumour angiogenesis regulation by the miR200 family. Nat. Commun. 4(2427) doi:10.1038/ ncomms3427 (2013).
10.4155/TDE.13.117 © 2013 Future Science Ltd
Ther. Deliv. (2013) 4(11), 1343–1345
News & Views
Lead story: miRNAs responsible for inhibiting angiogenesis in cancer pg 1343 Targeted nanoparticles exploit ion gradients for the repair of bone cracks pg 1344 Nanosized aspirin could extend benefits to help overcome resistance and nonresponse pg 1344 Spice turmeric found to be a key component to a potential anticancer drug pg 1345 Testing cancer drugs using chips pg 1345
– Written by Evgenia Koutsouki
ISSN 2041-5990
1343
News & Analysis
Targeted nanoparticles exploit ion gradients for the repair of bone cracks A team of scientists from The Pennsylvania State University (PA, USA) and Boston University (MA, USA) have demonstrated a novel method for the detection, targeting and repair of bone cracks, which involves the direct delivery of drugs by self-powered nanoparticles. Bone microcracks, which can lead to broken bones in patients with osteoporosis and other related conditions, generate ion gradients that can be utilized for active targeting and treatment. “When a crack occurs in a bone, it disrupts the minerals in the bone, which leach out as charged particles – as ions – that create an electric field, which pulls the negatively charged nanoparticles toward the crack,” explained Ayusman Sen, co-leader of the study and Professor of Chemistry at Pennsylvania State. “Our experiments have demonstrated that a biocompatible particle can quickly and naturally deliver an osteoporosis drug directly to newly cracked bone.” In order to test the novel delivery method, the group’s first series of experiments
comprised a model system using bone from a human tibia and femur to deliver fluorescent quantum dots made from a synthetic material. When analyzed under a microscope, this illustrated that the dots did move toward and aggregate on a newly formed crack. Further encouraging results were produced using natural biological materials, so the team performed further experiments with nanomotors made from both a biological and a synthetic material. The aim was to attach the biological material, in this case a drug used to treat osteoporosis, to a US FDA-approved synthetic material such as a nanotruck, to a crack in human bone. Using the ion gradient as a power source, the researchers hoped to develop a self-powered nanotruck that could effectively carry and deliver the osteoporosis drug, and have a good chance of being safe to use within the human body. On the results, Sen commented, “Our experiments show that this bio-safe nanomotor can in fact successfully carry the osteoporosis drug to a fresh crack in human bone.”
In a final series of experiments the nanodrug was tested on live human bone cells. Mark Grinstaff, Professor at Boston University, commented, “The treated bone cells increased in number as compared with those that were not treated with the osteoporosis drug, which confirms other studies that have demonstrated that this drug is effective in repairing human bones.” Sen concluded that “What makes our nanomotors different is that they can actively and naturally deliver medications to a targeted area. Current methods, in contrast, involve taking a drug and hoping that enough of it gets to where it is needed for healing.” – Written by James Potticary Sources: Yadav V, Freedman JD, Grinstaff M, Sen A. Bone-crack detection, targeting, and repair using ion gradients. Angew. Chem. Int. Ed. 52(42), 10997–11001 (2013); Penn State press release: Novel self-powered nanoparticles developed to deliver healing drugs directly to bone cracks: http://science.psu.edu/news-and-events/2013-news/ Sen8–2013–2
Nanosized aspirin could extend benefits to help overcome resistance and nonresponse For over a century, aspirin has been widely used in the treatment of a diverse array of indications. However, the therapeutic efficacy of this drug is severely diminished in cases of resistance and nonresponse, forcing some individuals to take more potent, prescription drugs that can have serious side effects. Now, researchers from Capital Medical University (Beijing, China) and Kaohsiung Medical University (Kaohsiung, Taiwan) have developed a covalently modified nanosized form of aspirin, which provides a strategy to overcome such problems. In the published study, the scientists focused on developing a small-molecule thrombus-targeting drug-delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), the RGD sequence of which recognizes and 1344
adheres to integrins, transmembrane receptors that bind to a number of extracellular matrix components. The targeting property of the RGD sequence toward activated platelets, in the case of aspirin, was therefore hypothesized to release aspirin in thrombi and inhibit its formation.
“The study demonstrated that the effective antithrombotic dose of nanosized aspirin is 16700-fold lower than that of the nonresponsive dose, and provides a strategy to mitigate aspirin resistance and nonresponse.” Following both in vitro and in vivo experiments, the scientists found that the Ther. Deliv. (2013) 4(11)
nanoparticles interacted with platelets present at the injured vascular endothelium and bound the receptor GPIIb/IIIa, releasing aspirin and blocking the conversion of arachidonic acid into prostaglandin G2 – selectively inhibiting platelet-induced aggregation. Overall, the study demonstrated that the effective antithrombotic dose of nanosized aspirin is 16700-fold lower than that of the nonresponsive dose, and provides a strategy to mitigate aspirin resistance and nonresponse. – Written by James Potticary Source: Jin S, Wang Y, Zhu H et al. Nanosized aspirin-Arg-Gly-Asp-Val: delivery of aspirin to thrombus by the target carrier Arg-GlyAsp-Val tetrapeptide. ACS Nano doi:10.1021/ nn402171v (2013) (Epub ahead of print). future science group
News & Analysis
Spice turmeric found to be a key component to a potential anticancer drug A collaborative study, led by Shijun Zhang from the Department of Medicinal Chemistry at Virginia Commonwealth University (VA, USA), has developed hybrid molecules containing structural components of thalidomide, a redundant drug previously used to treat morning sickness in pregnant women, and curcumin, more commonly known as the spice turmeric. The hybrid molecules designed and synthesized by the team demonstrated promising characteristics required for anticancer agents against multiple myeloma, a cancer of plasma cells, which currently affects 50,000 patients in the USA. Combinations of structural components of turmeric and thalidomide produced 15 hybrid molecules, in which all displayed different characteristics. In particular, two of the hybrid molecules displayed enhanced toxic effects against all cell lines.
In addition, the hybrid molecules showed enhanced anticancer activity against multiple myeloma cells than either compound administered alone, as explained by Steven Grant, “Overall, the combination of the spice and the drug was significantly more potent than either individually, suggesting that this hybrid strategy in drug design could lead to novel compounds with improved biological activities.”
“The combination of the spice and the drug was significantly more potent than either individually, suggesting that this hybrid strategy in drug design could lead to novel compounds with improved biological activities.”
Moreover, Grant, from the Department of Internal Medicine and Massey Cancer Center at Virginia Commonwealth University, explained that utilizing hybrid molecules can be advantageous in many ways, “Enhanced potency, reduced risk of developing drug resistance, improved pharmacokinetic properties, reduced cost and improved patient compliance are just a few of those advantages.” The results of this investigation open the way to further studies on these compounds and establishing their potential as anticancer agents against human multiple myeloma. – Written by Jessica Thorne Source: Liu K, Zhang D, Chojnacki J et al. Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma. Org. Biomol. Chem. 11(29), 4757–4763 (2013).
Testing cancer drugs using chips Targeted delivery of cancer drugs is an area of research that is receiving significant attention. Researchers at Lehigh University (PA, USA) are developing a method of testing the selectivity of cancer drugs in targeting specific cells using biochips coated with human endothelial cells. The team will use computer-aided design to etch the chips with channels that mimic the arteries and capillaries of the human lung. The chip will be engineered to stretch like a breathing lung, and will be coated with human endothelial cells treated with a chemical that induces inflammation in a similar manner to cancer. A blood solution containing antibody-conjugated nanoparticles
to deliver the drug will then be injected. A f luorescent marker will allow the researchers to observe the distribution of the nanoparticles, and quantify their interactions with cells to determine how successful the targeted delivery is. The drug-testing methods currently used have a number of limitations, including low translatability between animal models and humans. “The chip enables us to grow our own human cells and observe a drug’s effect on them in their natural environment,” describes Yaling Liu, one of the principal researchers. “This will make it possible to do screenings much more quickly and shorten the research cycle.” Other advantages of this method include
the low cost of the chips and the small drug doses required. The researchers also hope to reduce the time taken to run drug tests by running multiple tests simultaneously on a series of chips. Looking to the future, the team hopes to study how cancer cells metastasize by coating the chip with multiple layers of cells with a porous membrane. – Written by Kasumi Crews Source: Legigh University press release: Researchers advance the art of drug testing: w w w4.lehigh.edu/news/newsar ticle.aspx?Channel=%2FChannels%2 FN ews+2013&Work f lowIte mI D = 61ab b8c1-a4a7–41b3-a1c5-acf4a600135c
The editorial team welcomes suggestions for timely, relevant items for inclusion in the news. If you have newsworthy information, please contact: Hannah Stanwix, Managing Commissioning Editor Future Science Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK Tel.: +44 (0)20 8371 6090 E-mail: [email protected]
future science group
www.future-science.com
1345
News & Analysis
Highlighting the latest news and research in therapeutic delivery
miRNAs responsible for inhibiting angiogenesis in cancer
Contents
Family of miRNAs reported to prevent angiogenesis by inhibiting the action of cancer cytokines
A collaboration between scientists from the University of Texas (TX, USA) and the Karmanos Cancer Institute in Michigan (MI, USA), has elucidated the mechanism by which miR-200, a miRNA family, inhibits the epithelial-mesenchymal transition (EMT) in cancer. The team demonstrated that miR-200 inhibits angiogenesis by specifically targeting the chemokines IL-8 and chemokine (C-X-C motif) ligand 1 (CXCL1), two key molecules in tumor formation secreted by tumor endothelial and cancer cells. The group, led by Anil Sood, Professor of Gynecology, analyzed ovarian, renal, breast and non-small-cell lung cancer samples for expression of miR-200 family members. They found better survival rates for patients with lung, ovarian, kidney or triple-negative breast cancers who have high levels of miR-200 expression.
“The team used nanoparticles ... to deliver miR-200 into the tumor endothelium in mouse models of lung and triple-negative breast cancers. They observed reductions in primary tumor size and volume, and angiogenesis compared with untreated controls...”
CXCL1, and identified binding sites for miR200 on these genes. Data-mining studies in public miRNA and messenger RNA databases demonstrated a correlation of high IL-8 levels with poor survival rates, and low miR-200 levels with high IL-8 levels in lung, ovarian, kidney and triple-negative breast cancer. Interestingly, the team found elevated expression of IL-8 and CXCL1 in these cancer types compared with hormone-positive breast cancers. “We feel that these results are significant since they help to explain the divergent findings with regard to the miR-200 family in various cancer types,” commented Sood. miRNAs act by regulating gene expression. Until now it has been known that miR-200 inhibits EMT, a cellular transition associated with cancer progression and metastasis. During EMT, cells lose adhesion and increase motility by reduced expression of the adhesion molecule E-cadherin. This study shows for the first time a direct implication of miR-200 in angiogenesis. “There are several potential implications moving forward,” added Sood. “First, this work identifies cancer types (e.g., ovarian, renal, lung) where miR-200 could have therapeutic benefit. Second, conversely, it identifies cancer types where miR-200 would be unlikely to have therapeutic benefit (e.g., luminal breast cancer). Third, this work identified key downstream pathways affected by miR-200 related to angiogenesis and as such could be useful for biomarkers in monitoring therapeutic response.” Future studies will focus on exploring this and other miRNA pathways and their therapeutic potential, including testing the utility of miR-200 along with chemotherapy drugs.
The team used nanoparticles, previously developed in collaboration with Gabriel Lopez, Professor in the Department of Experimental Therapeutics at The University of Texas, to deliver miR-200 into the tumor endothelium in mouse models of lung and triple-negative breast cancers. They observed reductions in primary tumor size and volume, and angiogenesis compared with untreated controls, as well as sharp reductions in IL-8 levels and angiogenesis in ovarian cancer models. Delivering miR-200 directly to blood vessels by way of chitosan nanoparticles resulted in a 92% reduction in ovarian cancer metastases compared with controls. Studies in cell lines confirmed the effect of miR-200 in decreasing levels of IL-8 and
Source: Pecot CV, Rupaimoole R, Yang D et al. Tumour angiogenesis regulation by the miR200 family. Nat. Commun. 4(2427) doi:10.1038/ ncomms3427 (2013).
10.4155/TDE.13.117 © 2013 Future Science Ltd
Ther. Deliv. (2013) 4(11), 1343–1345
News & Views
Lead story: miRNAs responsible for inhibiting angiogenesis in cancer pg 1343 Targeted nanoparticles exploit ion gradients for the repair of bone cracks pg 1344 Nanosized aspirin could extend benefits to help overcome resistance and nonresponse pg 1344 Spice turmeric found to be a key component to a potential anticancer drug pg 1345 Testing cancer drugs using chips pg 1345
– Written by Evgenia Koutsouki
ISSN 2041-5990
1343
News & Analysis
Targeted nanoparticles exploit ion gradients for the repair of bone cracks A team of scientists from The Pennsylvania State University (PA, USA) and Boston University (MA, USA) have demonstrated a novel method for the detection, targeting and repair of bone cracks, which involves the direct delivery of drugs by self-powered nanoparticles. Bone microcracks, which can lead to broken bones in patients with osteoporosis and other related conditions, generate ion gradients that can be utilized for active targeting and treatment. “When a crack occurs in a bone, it disrupts the minerals in the bone, which leach out as charged particles – as ions – that create an electric field, which pulls the negatively charged nanoparticles toward the crack,” explained Ayusman Sen, co-leader of the study and Professor of Chemistry at Pennsylvania State. “Our experiments have demonstrated that a biocompatible particle can quickly and naturally deliver an osteoporosis drug directly to newly cracked bone.” In order to test the novel delivery method, the group’s first series of experiments
comprised a model system using bone from a human tibia and femur to deliver fluorescent quantum dots made from a synthetic material. When analyzed under a microscope, this illustrated that the dots did move toward and aggregate on a newly formed crack. Further encouraging results were produced using natural biological materials, so the team performed further experiments with nanomotors made from both a biological and a synthetic material. The aim was to attach the biological material, in this case a drug used to treat osteoporosis, to a US FDA-approved synthetic material such as a nanotruck, to a crack in human bone. Using the ion gradient as a power source, the researchers hoped to develop a self-powered nanotruck that could effectively carry and deliver the osteoporosis drug, and have a good chance of being safe to use within the human body. On the results, Sen commented, “Our experiments show that this bio-safe nanomotor can in fact successfully carry the osteoporosis drug to a fresh crack in human bone.”
In a final series of experiments the nanodrug was tested on live human bone cells. Mark Grinstaff, Professor at Boston University, commented, “The treated bone cells increased in number as compared with those that were not treated with the osteoporosis drug, which confirms other studies that have demonstrated that this drug is effective in repairing human bones.” Sen concluded that “What makes our nanomotors different is that they can actively and naturally deliver medications to a targeted area. Current methods, in contrast, involve taking a drug and hoping that enough of it gets to where it is needed for healing.” – Written by James Potticary Sources: Yadav V, Freedman JD, Grinstaff M, Sen A. Bone-crack detection, targeting, and repair using ion gradients. Angew. Chem. Int. Ed. 52(42), 10997–11001 (2013); Penn State press release: Novel self-powered nanoparticles developed to deliver healing drugs directly to bone cracks: http://science.psu.edu/news-and-events/2013-news/ Sen8–2013–2
Nanosized aspirin could extend benefits to help overcome resistance and nonresponse For over a century, aspirin has been widely used in the treatment of a diverse array of indications. However, the therapeutic efficacy of this drug is severely diminished in cases of resistance and nonresponse, forcing some individuals to take more potent, prescription drugs that can have serious side effects. Now, researchers from Capital Medical University (Beijing, China) and Kaohsiung Medical University (Kaohsiung, Taiwan) have developed a covalently modified nanosized form of aspirin, which provides a strategy to overcome such problems. In the published study, the scientists focused on developing a small-molecule thrombus-targeting drug-delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), the RGD sequence of which recognizes and 1344
adheres to integrins, transmembrane receptors that bind to a number of extracellular matrix components. The targeting property of the RGD sequence toward activated platelets, in the case of aspirin, was therefore hypothesized to release aspirin in thrombi and inhibit its formation.
“The study demonstrated that the effective antithrombotic dose of nanosized aspirin is 16700-fold lower than that of the nonresponsive dose, and provides a strategy to mitigate aspirin resistance and nonresponse.” Following both in vitro and in vivo experiments, the scientists found that the Ther. Deliv. (2013) 4(11)
nanoparticles interacted with platelets present at the injured vascular endothelium and bound the receptor GPIIb/IIIa, releasing aspirin and blocking the conversion of arachidonic acid into prostaglandin G2 – selectively inhibiting platelet-induced aggregation. Overall, the study demonstrated that the effective antithrombotic dose of nanosized aspirin is 16700-fold lower than that of the nonresponsive dose, and provides a strategy to mitigate aspirin resistance and nonresponse. – Written by James Potticary Source: Jin S, Wang Y, Zhu H et al. Nanosized aspirin-Arg-Gly-Asp-Val: delivery of aspirin to thrombus by the target carrier Arg-GlyAsp-Val tetrapeptide. ACS Nano doi:10.1021/ nn402171v (2013) (Epub ahead of print). future science group
News & Analysis
Spice turmeric found to be a key component to a potential anticancer drug A collaborative study, led by Shijun Zhang from the Department of Medicinal Chemistry at Virginia Commonwealth University (VA, USA), has developed hybrid molecules containing structural components of thalidomide, a redundant drug previously used to treat morning sickness in pregnant women, and curcumin, more commonly known as the spice turmeric. The hybrid molecules designed and synthesized by the team demonstrated promising characteristics required for anticancer agents against multiple myeloma, a cancer of plasma cells, which currently affects 50,000 patients in the USA. Combinations of structural components of turmeric and thalidomide produced 15 hybrid molecules, in which all displayed different characteristics. In particular, two of the hybrid molecules displayed enhanced toxic effects against all cell lines.
In addition, the hybrid molecules showed enhanced anticancer activity against multiple myeloma cells than either compound administered alone, as explained by Steven Grant, “Overall, the combination of the spice and the drug was significantly more potent than either individually, suggesting that this hybrid strategy in drug design could lead to novel compounds with improved biological activities.”
“The combination of the spice and the drug was significantly more potent than either individually, suggesting that this hybrid strategy in drug design could lead to novel compounds with improved biological activities.”
Moreover, Grant, from the Department of Internal Medicine and Massey Cancer Center at Virginia Commonwealth University, explained that utilizing hybrid molecules can be advantageous in many ways, “Enhanced potency, reduced risk of developing drug resistance, improved pharmacokinetic properties, reduced cost and improved patient compliance are just a few of those advantages.” The results of this investigation open the way to further studies on these compounds and establishing their potential as anticancer agents against human multiple myeloma. – Written by Jessica Thorne Source: Liu K, Zhang D, Chojnacki J et al. Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma. Org. Biomol. Chem. 11(29), 4757–4763 (2013).
Testing cancer drugs using chips Targeted delivery of cancer drugs is an area of research that is receiving significant attention. Researchers at Lehigh University (PA, USA) are developing a method of testing the selectivity of cancer drugs in targeting specific cells using biochips coated with human endothelial cells. The team will use computer-aided design to etch the chips with channels that mimic the arteries and capillaries of the human lung. The chip will be engineered to stretch like a breathing lung, and will be coated with human endothelial cells treated with a chemical that induces inflammation in a similar manner to cancer. A blood solution containing antibody-conjugated nanoparticles
to deliver the drug will then be injected. A f luorescent marker will allow the researchers to observe the distribution of the nanoparticles, and quantify their interactions with cells to determine how successful the targeted delivery is. The drug-testing methods currently used have a number of limitations, including low translatability between animal models and humans. “The chip enables us to grow our own human cells and observe a drug’s effect on them in their natural environment,” describes Yaling Liu, one of the principal researchers. “This will make it possible to do screenings much more quickly and shorten the research cycle.” Other advantages of this method include
the low cost of the chips and the small drug doses required. The researchers also hope to reduce the time taken to run drug tests by running multiple tests simultaneously on a series of chips. Looking to the future, the team hopes to study how cancer cells metastasize by coating the chip with multiple layers of cells with a porous membrane. – Written by Kasumi Crews Source: Legigh University press release: Researchers advance the art of drug testing: w w w4.lehigh.edu/news/newsar ticle.aspx?Channel=%2FChannels%2 FN ews+2013&Work f lowIte mI D = 61ab b8c1-a4a7–41b3-a1c5-acf4a600135c
The editorial team welcomes suggestions for timely, relevant items for inclusion in the news. If you have newsworthy information, please contact: Hannah Stanwix, Managing Commissioning Editor Future Science Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK Tel.: +44 (0)20 8371 6090 E-mail: [email protected]
future science group
www.future-science.com
1345
