Rallying Point – Harvard Medical School (registration)

§ June 2nd, 2017 § Filed under Nano Medicine Comments Off on Rallying Point – Harvard Medical School (registration)

Harvard Medical School researchers at Massachusetts General Hospital have identified a surprising new role for the immune cells called macrophages: improving the effectiveness ofnanoparticle-deliveredcancer therapies.

In theirScience Translational Medicinereport, the investigators describe finding how appropriately timed radiation therapy can improve the delivery of cancernanomedicinesas much as 600 percent by attracting macrophages to tumor blood vessels, which results in a transient burst of leakage from capillaries into the tumor.

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The field ofnanomedicinehas worked to improve selective drug delivery to tumors for over a decade, typically by engineering ever more advancednanomaterialsand often with mixed clinical success, said first authorMiles Miller, HMS instructor in radiology at Mass General. Rather than focusing on thenanoparticlesthemselves, we used in vivo microscopy to discover how to rewire the structure of the tumor itself to more efficiently accumulate a variety ofnanomedicinesalready in clinical use.

Encapsulating cancer drugs innanoparticlescan improve how a drug is absorbed, distributed, metabolized and excreted by extending a drugs presence in the circulatory system 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 drugs 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 enhancenanomedicinedelivery was not known. Answering those questions was the goal of the current study.

Finding that this combination of radiation andnanomedicineleads to synergistic tumor eradication in mice provides motivation for clinical trials that combine tumor rewiring using radiation therapy withnanomedicine” – Miles Miller

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 three to four 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 ofnanoparticles, 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, includingnanoparticles, 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 ofnanoparticles.

Combining radiation therapy with cyclophosphamidea DNA-damaging drug that enhances nanoparticle delivery to tumor cells through similar tumor-priming mechanismsled 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 andnanomedicineleads to synergistic tumor eradication in mice provides motivation for clinical trials that combine tumor rewiring using radiation therapy withnanomedicine, Miller said.

Most of the treatments andnanomedicinesemployed in this study are FDA approved for cancer treatment, so this combination treatment strategy could be tested in clinical trials relatively quickly, he added. And given the role of macrophages in this approach, we are particularly interested in combining tumor irradiation andnanomedicinewith immuno-oncology therapies.

This study was supported by National Institutes of Health grants UO1CA206997, K99CA207744, R01EB010011 and P50GM107618.

Adapted from a Mass Generalnewsrelease.

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Rallying Point – Harvard Medical School (registration)

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