Abstract:
Cancer is one of the leading causes of death in the U.S., and new approaches to
control cancer are constantly sought. This dissertation is comprised of two parts: (i)
improving the uptake and retention of gadolinium in tumors for potential gadoliniumneutron
capture therapy (Gd-NCT) and (ii) integration of gemcitabine or localized
irradiation into dsRNA therapy significantly enhanced the resultant anti-tumor
activity.
One of the key factors for a successful Gd-NCT is to deliver and maintain a
sufficient amount of Gd in tumor tissues (50-200 μg of Gd/g of wet tumor) during
neutron irradiation, which has proven to be challenging to achieve. A gadolinium-encapsulated
liposome (Gd-liposome) formulation was designed to address this need.
The formulation was prepared by complexing diethylenetriaminepentaacetic acid (Gd-
DTPA) with poly-L-lysine and then encapsulating the Gd-DTPA complexes intopegylated liposomes. The Gd-liposome formulation delivered as high as 159 μg of
pure Gd per g of wet tumor tissue into model tumors in mice. A liposome-in-thermosensitive
gel system that significantly extended the retention of the Gd in model
tumors in mice was also designed. These Gd delivery systems may be used to deliver
Gd into solid tumors for NCT and tumor imaging.
Despite of the potent tumoricidal activity of polyinosine-cytosine (e.g. poly(I:C)),
a synthetic dsRNA, in culture, its in vivo anti-tumor activity has proven to be limited.
Gemcitabine, a chemotherapy agent, or localized x-ray radiation was successfully
integrated into poly(I:C) therapy to improve the resultant anti-tumor activity in murine
tumor models. Combining gemcitabine with poly(I:C) synergistically inhibited the
growth of model tumors in mice and also generated a strong and durable tumorspecific
immune response. Alternatively, integrating localized x-ray radiation into
poly(I:C) therapy significantly delayed the tumor growth, but the combined activity
was synergistic only in mice with highly immunogenic tumors, indicating that the T
cell-mediated immunity was responsible for the synergy. The type I interferons (IFN-
α/β) induced by poly(I:C) played a critical role in the resultant anti-tumor activity.
These combination therapies may represent a promising approach to improve the
clinical outcomes of poly(I:C) therapy.
