“New Approaches to
the Prevention of Lung Tumor Recurrence Following Surgical Resection.”
Dr. Mark Grinstaff
Dr. Grinstaff presented on research conducted by his group
at the University of Boston. His group’s previous work includes developing
materials used in treatment of damaged ocular tissue; the development of
diblock structures; and cartilage imaging in 3D maps. Dr. Grinstaff’s current research
targets prevention of lung tumor recurrence following surgical resection
(surgical removal). His lecture encompassed three main topics: (1) the nature
of early stage lung cancer; (2) conditions concerning occurrence and treatment
of recurrent tumors in lung cancer patients; and (3) the new ideas and methods
being developed by his lab to treat these problems.
According to Dr. Grinstaff lung cancer is responsible for
over 162,000 deaths per year. Every year there are 215,000 new cases of lung
cancer. Stage 1 lung cancer is most commonly treated by surgical removal.
Keeping the “margin” area of the surgery clean is very difficult, and
recurrence is common in cases of lung cancer. The five year survival rate of
lung cancer is only 60%. Entire lobectomies are possible, but this effectively
decreases lung capacity by half and raises severe quality of life questions.
Margin sterilization is commonly performed via a technique
known as Brachytherapy. This involves the use of radioactive “seeds” in the
prevention of future recurrence. Recurrence rates drop from 19% to 2% in
patients who undergo Brachytherapy. However, the procedure involves a high
radiation risks to the clinical staff as well as the patient. Less risky
alternatives are desirable.
To this end Dr. Grinstaff has been interested in developing
chemical structures that can deliver anti-cancer medication (such as Paclitaxel
and Camptothecin) directly to the margin area without disrupting the healing
process. He discussed three creative possibilities: (1) enlarging nano-particles
(eNP’s); (2) chemical films; and (3) super-hydrophobic meshes.
ENP’s provide a variety of benefits, but in this case Dr.
Grinstaff has developed particles that respond to the pH level of a surrounding
fluid. His group is interested in creating nano-particles that carry a payload
of medication, cross cell membranes, and then respond to the internal pH level
of a cell. The response to the internal pH of the cell causes the nano-particle
to enlarge, thereby deploying its medicinal payload to the interior or the
cell. This means the eNP must be capable of transitioning from being a
hydrophobic particle to being a hydrophilic particle.
Dr. Grinstaff has been able to create eNP’s with these
behavior characteristics by using simple emulsion polymerization. The result is
an “expansile nanoparticle that is capable of undergoing a conformational
change: at a pH of 7 the particle is a solid sphere, but at a pH of 5 the
particle’s solidity diffuses into a larger corona enveloping a smaller core.
Dr. Grinstaff has been able to test the efficacy of these particles. He has
found that they do in fact swell in response to pH changes and they are capable
of entering cells. Most importantly they show positive results for diminishing
recurrent tumor growth in initial animal trials (involving the injection of
cancerous cells into lab mice). The eNP’s function both locally and generally,
being capable of moving through both cell walls and also through the lymph
system.
The second and third areas of Dr. Grinstaff’s research
(films and meshes) are closely related. This area of research began by looking
at the role of the surgical stapler. Surgical staplers are used to cut and seal
at the same time and prevent air leaks and enhance healing. The films and
meshes being developed by Dr. Grinstaff would be inserted into the wound and sealed
in with the surgical stapler. Bolus (a single ball) delivery of medication is
less effective than treatment over time. The goal is to affect multiple cell
cycles of cells involved in cancer resurgence.
Dr. Grinstaff’s meshes and films are made from a polyglerol.
Of interest to organic chemists is the ability to attach fatty acid chains to
the polyglycerol molecule, making a macro structure that resembles a kind of
oily film. This film can be used on exposed wound area or placed on open
systems. Dr. Grinstaff reported that Pactitasal-loaded films prevented local
tumor recurrence in vivo after surgery (in animal testing). The likely reason
for this is that the film is able to deliver a high concentration of drug to
the tumor site over a prolonged time. Histology has shown positive results.
The development of successfully entrapped hydrophobic
chemotherapy agents lead Dr. Grinstaff and his students to hypothesize and
develop the third mechanism mentioned above, “super-hydrophobic” materials for
drug delivery. These meshes create microscopic pockets of air against a layer
of cells, and this layer of air can be used as a barrier for drug release. Dr.
Grinstaff discussed the challenge in creatin such a delivery system, which lies
heavily in the degree angle of the mesh molecules with the target cells. Dr.
Grinstaff’s group has been able to create structures that create a contact
angle of up to 160 degrees.
Dr. Grinstaff's research has shown delayed cytotoxicity in
tests with the mesh. This is a positive result, as avoiding cytotoxicity in
treatment of cancer cells allows for prolonged treatment using anti-cancer
medication. In-vivo tests have yet to be conducted. Dr. Grinstaff hypothesized
that mesh “sandwiches” might be developed and deployed. These would have the
added benefit of providing physical reinforcement for the lung.
In an additional development, these meshes can be “activated”
by using high frequency ultrasound. The mesh can be inserted into a surgical
margin in a “non-deployed” state at first, when it is important to keep the
harmful effects of anti-cancer medication from harming healthy cells. When the
wound area has healed to a sufficient degree a burst of high frequency
ultrasound can cause the medicinally-loaded meshes to release their chemical
payloads into the directed areas.
Dr. Grinstaff’s conclusion to this lecture came as a simple
question, “why?” His goal is to help wounds heal without the interference from
cancer cells. He hopes the development of these technologies can greatly reduce
the recurrence of lung cancer in lung cancer patients. He also notes that these
technologies have the potential to be used for the deployment of other kinds of
treatment, and are not limited to cancer treatment.
No comments:
Post a Comment