(783c) Embolic Polylactide-Co-Glycolide Microspheres for Image-Guided,Transcathter Delivery of Sorafenib to Hepatocellular Carcinoma | AIChE

(783c) Embolic Polylactide-Co-Glycolide Microspheres for Image-Guided,Transcathter Delivery of Sorafenib to Hepatocellular Carcinoma


Chen, J. - Presenter, Northwestern University
Shea, L. D., Northwestern University
Larson, A., Northwestern University

Introduction: Hepatocellular carcinoma (HCC) is the most
common form of primary liver cancer and most patients are not eligible for
potentially curative treatments (resection, transplant) as the cancer is often
diagnosed during later stages.  Therefore, these patients undergo palliative
treatments such as transcatheter therapies.  These therapies involve having
doctors place a catheter in the femoral artery and using image guidance to
guide it to tumor feeding branches of the hepatic artery.  Once the catheter is
placed, chemotherapy or radiation therapy is given along with embolic agents to
help contain the therapy locally to the tumor as well as to prevent blood flow
to the tumor to help starve it. The purpose of our studies is to develop a drug
delivery system to allow for sorafenib to be delivered as part of a
transcatheter therapy via an embolic polymer microsphere bead.  Additionally,
we have added an iron oxide component to serve as a contrast agent to allow for
magnetic resonance imaging (MRI) of the delivery.

A more recent therapy for HCC is sorafenib (brand name
Nexavar), which is a multikinase inhibitor that was approved by the FDA in
2007.  It is currently formulated as an oral tablet, and therefore, the
systemic administration is associated with severe side effects such as
diarrhea, hand foot syndrome (severe rashes of the hands and feet), and
hypertension.  Therefore, patients do not tolerate sorafenib well.  Re-formulating
sorafenib for delivery using transcatheter techniques would improve patient
tolerance.  Furthermore, it would also allow for increased does at the tumor
and an added embolic effect to improve therapy.

Methods: We have chosen polylactide-co-glycolide (PLG) as
our platform and we employed a single emulsion/solvent evaporation method to
fabricate our microspheres to co-encapsulate the sorafenib and a hydrophobic
iron oxide.  We then characterized the size and morphology using microscopy and
Image J software analysis.   Sorafenib and iron oxide loading were
characterized with high performance liquid chromatography and inductively
coupled plasma mass spectroscopy, respectively.  Sorafenib and iron oxide release
were also monitored using similar methods.   The contrast effect these
microspheres have under MRI was monitored in vitro using a 7 Tesla MRI
scanner.  Lastly, the microspheres were injected to tumor feeding arteries
transcather in a rabbit VX2 animal model to mimic clinical delivery.  The
rabbit was then imaged in the same 7 Tesla MRI scanner to visualize the
distribution of the microspheres.  After imaging, the rabbit was sacrificed and
sections of the liver, tumors, stomach and lungs were harvested and submitted
for histology with Prussian blue staining for iron to confirm the microsphere biodistribution.

Results: The resulting microspheres were of an average
diameter of 22.7 microns.  Iron oxide content and sorafenib content were 0.209%
w/w) and 14.0% (w/w) respectively.  The release study indicated slow burst
release whereas 2.27% of the loaded sorafenib released within 3 days.  In
MRI imaging showed that increasing concentrations of the microspheres
from 0-20 mg/mL caused a reduction in T2* from 111 to 8.13 ms.  Lastly, after
infusion of the microspheres into the rabbit, we were able to depict the
microspheres under MRI as areas of darkening near the tumors.  Prussian blue
histology to confirm microsphere biodistribution indicated that the tumors
showed high staining at the tumors and minimal staining in the normal liver,
stomach and lungs (stomach and lungs are of concern as microsphere distribution
to those tissues can cause problems).

Conclusion: These rigorous characterization studies show
that embolic PLG microspheres can co-encapsulate sorafenib and iron oxide. 
These microspheres can also be delivered locally to liver tumors through a
catheter to ultimately produce a therapeutic response.