Yale Drug-Loaded Nanogel Delivers Combination Cancer Therapy

Yale Drug-Loaded Nanogel Delivers Combination Cancer Therapy

Yale University scientists have developed a new mechanism for attacking cancerous tumors that intensifies the body’s immune response while simultaneously weakening the tumor’s ability to resist it.

“We believe this is a paradigm-changing immunotherapeutic method for cancer therapy,” said Tarek M. Fahmy, a bioengineer at Yale and the project’s principal investigator. “In essence, it’s a one-two punch strategy that seems to work well for melanoma and may work even better with other cancers.”

The researchers report results July 15 online in the journal Nature Materials. Dr. Richard A. Flavell of Yale School of Medicine and the Howard Hughes Medical Institute collaborated on the project. Flavell is also a member of Yale Cancer Center.

Tumors — in this case metastatic melanomas, or spreading skin cancers — are adept at overcoming their host’s natural defenses, in part by emitting agents that disrupt production and operation of the immune system.

The Yale team developed a new biodegradable nanoparticle that delivers a combination of two very different therapeutic agents to tumor sites, gradually releasing the agents into the tumor vasculature. One agent, a large soluble protein called a cytokine, stimulates the body’s innate immune response. The other, a small-molecule inhibitor, interferes with the tumor’s ability to suppress the immune response. Other drug combinations are possible.

In tests on live mice, the double-loaded particle, called a nanogel, significantly delayed tumor growth and increased survival, the researchers report. They administered the nanogels intravenously and, in separate experiments, directly into the tumors. Further animal tests are planned.

The main challenge researchers faced was devising a particle that enabled gradual, sustained release of two therapeutic agents with very different properties: the protein, which readily dissolves in the body, and the small-molecule drug, which doesn’t. Researchers describe the materials and unique structure of their solution in the Nature Materials paper.

They exclusively used components already approved by the U.S. Food and Drug Administration. This could potentially expedite future experiments with other ingredients and human trials, they said.

Other authors are Jason Park, Stephen H. Wrzesinski, Eric Stern, Michael Look, Jason Criscione, Ragy Ragheb, Steven M. Jay, Stacey L. Demento, Atu Agawu, Paula Licona Limon, Anthony F. Ferrandino, David Gonzalez, and Ann Habermann, all of Yale.

Support for the project was provided by the National Institutes of Health; the National Science Foundation; Yale University; the Howard Hughes Medical Institute; and the PEW Charitable Trust.

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-? (TGF-?), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-? inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

Researchers from Yale and Howard Hughes Medical Institute are reporting in journal Nature Materials on a novel new biodegradable nanogel that is capable of delivering two complementary therapeutic agents to tumors. Cytokine is used to promote immune activity around the target site and a small-molecule inhibitor interferes with the cancer’s response to the immune system. The current molecule combination is showing effectiveness in fighting metastatic melanomas, but other drug combinations should be deliverable by the new nanogel to provide therapy for a variety of cancers.

“We believe this is a paradigm-changing immunotherapeutic method for cancer therapy,” said Tarek M. Fahmy, a bioengineer at Yale and the project’s principal investigator. “In essence, it’s a one-two punch strategy that seems to work well for melanoma and may work even better with other cancers.”

In tests on live mice, the double-loaded particle, called a nanogel, significantly delayed tumor growth and increased survival, the researchers report. They administered the nanogels intravenously and, in separate experiments, directly into the tumors. Further animal tests are planned.

The main challenge researchers faced was devising a particle that enabled gradual, sustained release of two therapeutic agents with very different properties: the protein, which readily dissolves in the body, and the small-molecule drug, which doesn’t.

They exclusively used components already approved by the U.S. Food and Drug Administration. This could potentially expedite future experiments with other ingredients and human trials, they said.

Source : http://news.yale.edu/2012/07/16/drug-loaded-nanogel-yale-researchers-attack-cancerous-tumors

Related Posts Plugin for WordPress, Blogger...
Be Sociable, Share!

About the Author

has written 1822 posts on this blog.

Copyright © 2017 Medical Technology & Gadgets Blog MedicalBuy.net. All rights reserved.
Proudly powered by WordPress. Developed by Deluxe Themes