This illustration depicts the 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 |
Cancers are notorious for secreting chemicals that confuse the immune system and thwart biological defenses.
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-? (TGF-?), 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-?. Our strategy is to ‘dry-up’ that moat by neutralizing
the TGF-?. 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-? 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-? 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 (a dual-layer, water-phobic
molecule such as fats and oils) 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-?
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.
Source: National Science Foundation
