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
Cancers are notorious for secreting chemicals that confuse the immune
system and thwarting 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-β (TGF-β), 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-β. Our strategy is to 'dry-up' that
moat by neutralizing the TGF-β. 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-β 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-β 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-β 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.
More information: DOI: 10.1038/nmat3355
Provided
by National
Science Foundation
No comments:
Post a Comment