Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Elegant delivery

16.07.2012
Sophisticated technique for delivering multiple cancer treatments may solve frustrating hurdle for combinatorial drug therapies

Cancers are notorious for secreting chemicals that confuse the immune system and thwarting biological defenses.


This illustration depicts a nanolipogel, developed at Yale University with NSF support, administering its immunotherapy cargo. The light-blue spheres within the blood vessels and the cutaway sphere in the foreground, are the nanolipogels (NLGs). As the NLGs break down, they release IL-2 (the green specks), which helps recruit and activate a body's immune response (the purple, sphere-like cells). The tiny, bright blue spheres are the additional treatment, a cancer drug that inhibits TGF-beta (one of the cancer's defense chemicals). Credit: Nicolle Rager Fuller, NSF

To counter that effect, some cancer treatments try to neutralize the cancer's chemical arsenal and boost a patient's immune response--though attempts to do both at the same time are rarely successful.

Now, researchers have developed a novel system to simultaneously deliver a sustained dose of both an immune-system booster and a chemical to counter the cancer's secretions, resulting in a powerful therapy that, in mice, delayed tumor growth, sent tumors into remission and dramatically increased survival rates.

The researchers, all from Yale University, report their findings in the July 15, 2012, issue of Nature Materials.

The new immunotherapy incorporates well-studied drugs, but delivers them using nanolipogels (NLGs), a new drug transport technology the researchers designed. The NLGs are nanoscale, hollow, biodegradable spheres, each one capable of accommodating large quantities of chemically diverse molecules.

The spheres appear to accumulate in the leaky vasculature, or blood vessels, of tumors, releasing their cargo in a controlled, sustained fashion as the spherule walls and scaffolding break down in the bloodstream.

For the recent experiments, the NLGs contained two components: an inhibitor drug that counters a particularly potent cancer defense called transforming growth factor-â (TGF-â), and interleukin-2 (IL-2), a protein that rallies immune systems to respond to localized threats.

"You can think of the tumor and its microenvironment as a castle and a moat," says Tarek Fahmy, the Yale University engineering professor and NSF CAREER grantee who led the research. "The 'castles' are cancerous tumors, which have evolved a highly intelligent structure--the tumor cells and vasculature. The 'moat' is the cancer's defense system, which includes TGF-â. Our strategy is to 'dry-up' that moat by neutralizing the TGF-â. We do that using the inhibitor that is released from the nanolipogels. The inhibitor effectively stops the tumor's ability to stunt an immune response."

At the same time, the researchers boost the immune response in the region surrounding the tumor by delivering IL-2--a cytokine, which is a protein that tells protective cells that there is a problem--in the same drug delivery vehicle. "The cytokine can be thought of as a way to get reinforcements to cross the dry moat into the castle and signal for more forces to come in," adds Fahmy. In this case, the reinforcements are T-cells, the body's anti-invader 'army.' By accomplishing both treatment goals at once, the body has a greater chance to defeat the cancer.

The current study targeted both primary melanomas and melanomas that have spread to the lung, demonstrating promising results with a cancer that is well-suited to immunotherapy and for which radiation, chemotherapy and surgery tend to prove unsuccessful, particularly when metastatic. The researchers did not evaluate primary lung cancers in this study.

"We chose melanoma because it is the 'poster child' solid tumor for immunotherapy," says co-author Stephen Wrzesinski, now a medical oncologist and scientist at St. Peter's Cancer Center in Albany, N.Y. "One problem with current metastatic melanoma immunotherapies is the difficulty managing autoimmune toxicities when the treatment agents are administered throughout the body. The novel nanolipogel delivery system we used to administer IL-2 and an immune modulator for blocking the cytokine TGF-â will hopefully bypass systemic toxicities while providing support to enable the body to fight off the tumor at the tumor bed itself."

Simply stated, to attack melanoma with some chance of success, both drugs need to be in place at the same location at the same time, and in a safe dosage. The NLGs appear to be able to accomplish the dual treatment with proper targeting and a sustained release that proved safer for the animals undergoing therapy.

Critical to the treatment's success is the ability to package two completely different kinds of molecules--large, water-soluble proteins like IL-2 and tiny, water-phobic molecules like the TGF-â inhibitor-into a single package.

While many NLGs are injected into a patient during treatment, each one is a sophisticated system composed of simple-to-manufacture, yet highly functional, parts. The outer shell of each NLG is made from an FDA-approved, biodegradable, synthetic lipid that the researchers selected because it is safe, degrades in a controlled manner, is sturdy enough to encapsulate a drug-scaffolding complex, and is easy to form into a spherical shell.

Each shell surrounds a matrix made from biocompatible, biodegradable polymers that the engineers had already impregnated with the tiny TGF-â inhibitor molecules. The researchers then soaked those near-complete spheres in a solution containing IL-2, which gets entrapped within the scaffolding, a process called remote loading.

The end result is a nanoscale drug delivery vehicle that appears to fit the narrow parameters necessary for successful treatment. Each NLG is small enough to travel through the bloodstream, yet large enough to get entrapped in leaky cancer blood vessels.

The NLG lipid shells have the strength to carry drugs into the body, yet are degradable so that they can deliver their cargo. And most critically, the spherules are engineered to accommodate a wide range of drug shapes and sizes. Ultimately, such a system could prove powerful not only for melanoma, but for a range of cancers.

Media Contacts

Joshua A. Chamot, NSF (703) 292-7730 jchamot@nsf.gov

Eric Gershon, Yale University (203) 432-8555 eric.gershon@yale.edu

Program Contacts

Kaiming Ye, NSF (703) 292-2161 kye@nsf.gov

Principal Investigators

Tarek Fahmy, Yale University (203) 432-1043 tarek.fahmy@yale.edu

Co-Investigators

Stephen Wrzesinski, St. Peter's Cancer Care Center (518) 525-6418 SWrzesinski@stpetershealthcare.org

Josh Chamot | EurekAlert!
Further information:
http://www.nsf.gov

Further reports about: Cancer Elegant NLG NSF blood vessel cancerous tumor immune system lung cancer

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Storage & Transport of highly volatile Gases made safer & cheaper by the use of “Kinetic Trapping"

Augsburg chemists present a new technology for compressing, storing and transporting highly volatile gases in porous frameworks/New prospects for gas-powered vehicles

Storage of highly volatile gases has always been a major technological challenge, not least for use in the automotive sector, for, for example, methane or...

Im Focus: Disrupting crystalline order to restore superfluidity

When we put water in a freezer, water molecules crystallize and form ice. This change from one phase of matter to another is called a phase transition. While this transition, and countless others that occur in nature, typically takes place at the same fixed conditions, such as the freezing point, one can ask how it can be influenced in a controlled way.

We are all familiar with such control of the freezing transition, as it is an essential ingredient in the art of making a sorbet or a slushy. To make a cold...

Im Focus: Micro energy harvesters for the Internet of Things

Fraunhofer IWS Dresden scientists print electronic layers with polymer ink

Thin organic layers provide machines and equipment with new functions. They enable, for example, tiny energy recuperators. In future, these will be installed...

Im Focus: Dynamik einzelner Proteine

Neue Messmethode erlaubt es Forschenden, die Bewegung von Molekülen lange und genau zu verfolgen

Das Zusammenspiel aus Struktur und Dynamik bestimmt die Funktion von Proteinen, den molekularen Werkzeugen der Zelle. Durch Fortschritte in der...

Im Focus: Dynamics of individual proteins

New measurement method allows researchers to precisely follow the movement of individual molecules over long periods of time

The function of proteins – the molecular tools of the cell – is governed by the interplay of their structure and dynamics. Advances in electron microscopy have...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

5th International Conference on Cellular Materials (CellMAT), Scientific Programme online

02.10.2018 | Event News

Major Project: The New Silk Road

01.10.2018 | Event News

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

 
Latest News

Physics: Not everything is where it seems to be

15.10.2018 | Physics and Astronomy

Microfluidic molecular exchanger helps control therapeutic cell manufacturing

15.10.2018 | Life Sciences

Link between Gut Flora and Multiple Sclerosis Discovered

15.10.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>