This thesis advances the use of nanopartic1es as multifunctional agents for
molecularly-targeted cancer imaging and photothermal therapy. Cancer mortality has
remained relatively unchanged for several decades, indicating a significant need for
improvements in care. Researchers are evaluating strategies incorporating nanopartic1es
as exogenous energy absorbers to deliver heat capable of inducing cell death selectively
to tumors, sparing normal tissue. Molecular targeting of nanopartic1es is predicted to
improve photothermal therapy by enhancing tumor retention. This hypothesis is
evaluated with two types of nanopartic1es.
The nanopartic1es utilized, silica-gold nanoshells and gold-gold sulfide
nanopartic1es, can convert light energy into heat to damage cancerous cells. For in vivo
applications nanopartic1es are usually coated with poly(ethylene glycol) (PEG) to
increase blood circulation time. Here, heterobifunctional PEG links nanopartic1es to
targeting agents (antibodies and growth factors) to provide cell-specific binding. This
approach is evaluated through a series of experiments.
In vitro, antibody-coated nanopartic1es can bind breast carcinoma cells expressing
the targeted receptor and act as contrast agents for multiphoton microscopy prior to
inducing cell death via photoablation. Furthermore, antibody-coated nanopartic1es can
bind tissue ex vivo at levels corresponding to receptor expression, suggesting they should
bind their target even in the complex biological milieu. This is evaluated by comparing
the accumulation of antibody-coated and PEG-coated nanoparticles in subcutaneous
glioma tumors in mice. Contrary to expectations, antibody targeting did not yield more
nanoparticles within tumors. Nevertheless, these studies established the sensitivity of
glioma to photothermal therapy; mice treated with PEG-coated nanoshells experienced
57% complete tumor regression versus no regression in control mice. Subsequent
experiments employed intracranial tumors to better mimic the clinical setting. These
tumors are highly vascularized, so nanoparticles were addressed toward receptors
abundantly expressed on tumor vessels using growth factors as a novel targeting strategy.
Photothermal therapy with these vascular-targeted nanoparticles disrupted tumor vessels,
leading to a 2.2-fold prolongation of median survival versus control mice.
This work confirms that nanoparticle surface coating can affect biodistribution
and therapeutic efficacy. With continued optimization of molecular targeting strategies,
imaging and photothermal therapy mediated by nanoshells and gold-gold sulfide
nanoparticles may offer an effective alternative to conventional cancer management
