Radiation therapy, macrophages improve efficacy of nanoparticle-delivered cancer therapyMay 31, 2017
A Massachusetts General Hospital (MGH) research team has identified a surprising new role for the immune cells called macrophages -- improving the effectiveness of nanoparticle-delivered cancer therapies. In their Science Translational Medicine report, the investigators describe finding how appropriately timed radiation therapy can improve the delivery of cancer nanomedicines as much as 600 percent by attracting macrophages to tumor blood vessels, which results in a transient "burst" of leakage from capillaries into the tumor.
"The field of nanomedicine has worked to improve selective drug delivery to tumors for over a decade, typically by engineering ever more advanced nanomaterials and often with mixed clinical success," says lead author Miles Miller, PhD, of the MGH Center for Systems Biology. "Rather than focusing on the nanoparticles themselves, we used in vivo microscopy to discover how to rewire the structure of the tumor itself to more efficiently accumulate a variety of nanomedicines already in clinical use."
Encapsulating cancer drugs in nanoparticles can improve pharmacokinetics -- how a drug is absorbed, distributed, metabolized and excreted -- by extending a drug's presence in the circulation and avoiding the toxic solvents used in infusion chemotherapy. But in clinical practice, delivering nanoencapsulated drugs into patients' tumors has been challenging, largely because of known factors in the microenvironment of the tumor. High pressures within tumors and low permeability of tumor blood vessels limit the passage of any drugs from the circulation into tumor cells.
A 2015 study by Miller and his colleagues showed that tumor-associated macrophages can improve delivery of nanoparticle-based therapies to tumor cells, and radiation therapy is known to increase the permeability of tumor vessels. But exactly how these effects are produced and how they could be combined to enhance nanomedicine delivery was not known. Answering those questions was the goal of the current study.
Experiments in mouse models of cancer revealed that radiation therapy produced important changes in the tumor microenvironment -- including greater blood vessel size and permeability and an increase in the number of macrophages relative to tumor cells. These changes did not appear until 3 to 4 days after administration of radiation therapy and disappeared by day 11. Analysis of patient biopsy samples taken before and several days after radiation therapy for breast or cervical cancer revealed significant macrophage expansion in post-radiation samples, with the greatest increases in patients receiving the highest radiation dosage.
Additional mouse studies showed that, beginning three days after radiation therapy, the uptake of nanoparticles but not of solvent-delivered drugs approximately doubled. High-resolution in vivo microscopy revealed that increases in vascular permeability occurred erratically, with periods of low permeability interrupted by a bursting of vascular contents, including nanoparticles, into the tumors. The rate of bursting increased three days after radiation and was higher on larger blood vessels with adjacent macrophages. Removal of macrophages prevented the radiation-induced changes and the increased uptake of nanoparticles. Combining radiation therapy with cyclophosphamide - a DNA-damaging drug that enhances nanoparticle delivery to tumor cells through similar tumor-priming mechanisms - led to even greater nanoparticle uptake.
Testing the therapeutic effect of combining radiation therapy with a nanoparticle-encased chemotherapy drugs in a mouse model confirmed the efficacy of the strategy and the key role of macrophages. While combining radiation with a solvent-based drug had no benefit compared with radiation alone, delivery of a nanoencapsulated version of the same drug three days after radiation therapy eliminated most tumors, an effect that was significantly reduced if macrophages were depleted.
"Finding that this combination of radiation and nanomedicine leads to synergistic tumor eradication in mice provides motivation for clinical trials that combine tumor rewiring using radiation therapy with nanomedicine," says Miller, who is an instructor in Medicine at Harvard Medical School. "Most of the treatments and nanomedicines employed in this study are FDA approved for cancer treatment, so this combination treatment strategy could be tested in clinical trials relatively quickly. And given the role of macrophages in this approach, we are particularly interested in combining tumor irradiation and nanomedicine with immuno-oncology therapies."
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
Massachusetts General Hospital
Related Nanoparticles Articles:
A team of chemists led by Carnegie Mellon's Rongchao Jin has for the first time conducted site-specific surgery on a nanoparticle.
The way that nanoparticles behave in the environment is extremely complex.
KAUST researchers reveal how small organic 'citrate' ions can stabilize gold nanoparticles, assisting research on the structures' potential.
Twenty-five years have passed since the publication of the first work on solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as a system for delivering drugs.
In shampoo ads, hair always looks like a shiny, smooth surface.
Scientists at the University of Basel have developed nanoparticles which can serve as efficient contrast agents for magnetic resonance imaging.
Cancer treatments based on laser irridation of tiny nanoparticles that are injected directly into the cancer tumor are working and can destroy the cancer from within.
Zap a tumor with radiation to trigger expression of a molecule, then attack that molecule with a drug-loaded nanoparticle.
Use of nanoparticles in many applications, e.g. for catalysis, relies on the surface area of the particles.
Scientists have devised a triple-stage 'cluster bomb' system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor.
Related Nanoparticles Reading:
Nanoparticles: From Theory to Application
by GÃ¼nter Schmid (Editor)
Very small particles are able to show astonishing properties. For example, gold atoms can be combined like strings of pearls, while nanoparticles can form one-, two- and three-dimensional layers. These assemblies can be used, for instance, as semiconductors, but other electronic as well as optical properties are possible.
An introduction to the booming field of "nanoworld" or "nanoscience", from fundamental principles to their use in novel applications.
With its clear structure and comprehensive coverage, backed by numerous examples from recent literature, this is a prime reference... View Details
Nanoparticles - Nanocomposites Â– Nanomaterials: An Introduction for Beginners
by Dieter Vollath (Author)
Meeting the demand for a readily understandable introduction to nanomaterials and nanotechnology, this textbook specifically addresses the needs of students - and engineers - who need to get the gist of nanoscale phenomena in materials without having to delve too deeply into the physical and chemical details.
The book begins with an overview of the consequences of small particle size, such as the growing importance of surface effects, and covers successful, field-tested synthesis techniques of nanomaterials. The largest part of the book is devoted to the particular magnetic, optical,... View Details
Characterization of Nanoparticles Intended for Drug Delivery (Methods in Molecular Biology)
by Scott E. McNeil (Editor)
This second edition volume expands on the first edition by providing up-to-date protocols to characterize nanomaterials used as drug delivery agents. The chapters in this book are divided into 5 parts and cover topics such as: advances and obstacles in nanomedicine research; methods to test sterility and endotoxin, physicochemical features, immunological effects, drug release, and in vivo efficacy. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents,... View Details
Nanoparticle Superheroes Defeat Evil Microbes
by Anna Rutkowski (Author)
Anna Rutkowski, a senior at Cardinal Wuerl North Catholic, partnered with Dr. Teri Dankovich of Folia Water. She wants to inspire kids with the VERY inspiring story of Dr. Teri's wonderful paper that makes polluted water drinkable for, potentially, millions of children and families around the world. Read, be inspired, and help save a life. View Details
Lipid Nanoparticles: Production, Characterization and Stability (SpringerBriefs in Pharmaceutical Science & Drug Development)
by Rohan Shah (Author), Daniel Eldridge (Author), Enzo Palombo (Author), Ian Harding (Author)
What are lipid nanoparticles? How are they structured? How are they formed? What techniques are best to characterize them? How great is their potential as drug delivery systems? These questions and more are answered in this comprehensive and highly readable work on lipid nanoparticles. This work sets out to provide the reader with a clear and understandable understanding of the current practices in formulation, characterization and drug delivery of lipid nanoparticles. A comprehensive description of the current understanding of synthesis, characterization, stability... View Details
Magnetic Nanoparticles: From Fabrication to Clinical Applications
by Nguyen TK Thanh (Editor), Mostafa A. El Sayed (Editor)
Offering the latest information in magnetic nanoparticle (MNP) research, Magnetic Nanoparticles: From Fabrication to Clinical Applications provides a comprehensive review, from synthesis, characterization, and biofunctionalization to clinical applications of MNPs, including the diagnosis and treatment of cancers.
This book, written by some of the most qualified experts in the field, not only fills a hole in the literature, but also bridges the gaps between all the different areas in this field.
Translational research on tailored magnetic... View Details
by Sergey P. Gubin (Editor)
This interdisciplinary approach to the topic brings together reviews of the physics, chemistry, fabrication and application of magnetic nanoparticles and nanostructures within a single cover. With its discussion of the basics as well as the most recent developments, and featuring many examples of practical applications, the result is both a clear and concise introduction to the topic for beginners and a guide to relevant comprehensive physical phenomena and essential technological applications for experienced researchers. View Details
Plasmon Resonances in Nanoparticles (World Scientific Series in Nanoscience and Nanotechnology)
by Isaak D Mayergoyz (Author)
This unique volume provides a broad introduction to plasmon resonances in nanoparticles and their novel applications. Here, plasmon resonances are treated as an eigenvalue problem for specific boundary integral equations and general physical properties of plasmon spectrum are studied in detail. The coupling of incident radiation to specific plasmon modes, the time dynamics of their excitation and dephasing are also analytically treated. Finally, the applications of plasmon resonances to SERS, light controllability (gating) of plasmon resonances in semiconductor nanoparticles, the use of... View Details
Nanoparticle Technology Handbook, Second Edition
by Makio Naito (Editor), Masuo Hosokawa (Editor), Toyokazu Yokoyama (Editor), Kiyoshi Nogi (Editor)
The updated and expanded second edition of the Nanoparticle Technology Handbook is an authoritative reference providing both the theory behind nanoparticles and the practical applications of nanotechnology. The second edition is thoroughly updated and expanded with sixteen new chapters, providing a reference much broader in scope than the previous edition. Over 140 experts in nanotechnology and/or particle technology contributed to this new edition.
Nanoparticle technology is a new and revolutionary technology, which is increasingly being used in electronic devices... View Details
Nanoparticle Engineering for Chemical-Mechanical Planarization: Fabrication of Next-Generation Nanodevices
by Ungyu Paik (Author), Jea-Gun Park (Author)
In the development of next-generation nanoscale devices, higher speed and lower power operation is the name of the game. Increasing reliance on mobile computers, mobile phone, and other electronic devices demands a greater degree of speed and power. As chemical mechanical planarization (CMP) progressively becomes perceived less as black art and more as a cutting-edge technology, it is emerging as the technology for achieving higher performance devices.
Nanoparticle Engineering for Chemical-Mechanical Planarization explains the physicochemical properties of... View Details