Nanotechnology has the potential to deliver multiple imaging and therapeutic agents to the "right place at the right time". This could dramatically improve treatment responses in cancer which
have been so far, dismal as well as allow us to monitor this response online. Pancreatic cancer (PanCa) has a poor prognosis with a 5-year survival rate of only 5% and there is a desperate need
for effective treatments. Photodynamic therapy (PDT) has shown promising results in treating PanCa. Mechanism-based combinations with PDT have enhanced treatment outcome. Agents
tested with PDT include Avastin, an antibody against vascular endothelial growth factor (VEGF) which is approved for treating various cancers. Here, we investigate the effect of neutralizing
intracellular VEGF using nanotechnology for the delivery of Avastin in combination with PDT.
For this we used a construct called "nanocells" in which the photosensitizer was trapped inside polymer nanoparticles and these, with Avastin, were then encapsulated inside liposomes.
Simultaneous delivery of drugs in nano-constructs could improve the treatment response of mechanism based combination therapies against cancer. Our studies demonstrate significant enhancement in treatment outcomes when nanocell-based PDT is combined with Avastin in
orthotopic PanCa mouse models. We propose a new paradigm for Avastin-based therapy by combining intracellular delivery of the antibody and PDT using nanotechnology for treating PanCa.
Delivery of therapeutic agents to solid tumors is challenging, and the issues that govern this can be distilled down into
parameters which allow computational modeling. In this paper, the basic rate equations and diffusion kernel for the time
and space modeling of delivery are developed, along with an analytical solution to this equation. The model is then used
to compare delivery of Avastin antibody relative to delivery encapsulated in a nanocell delivery vehicle. The key factors
are the plasma clearance or excretion rates, and the binding, or not, as it transports into the tumor tissue. A reduction in
the plasma clearance rate inherently increases available delivery over time, and additionally the reduction in binding
from antibody to nanocell allows higher penetration into the tumor at the longer circulation times.
Nanomedicine is beginning to impact the treatment of several diseases and current research
efforts include development of integrated nano-constructs (theranostics) which serve as probes
for imaging and therapy in addition to delivering macromolecules intracellularly. In cancer, there
is a vital unmet need for effective alternative treatments with high specificity and low systemic
toxicity. This can be achieved by targeting key molecular markers associated with cancer cells
with reduced effective drug doses. Here, we show an innovative proof-of-principle approach for
efficient killing of proliferating ovarian cancer cells by inactivating a protein associated with cell
proliferation namely, the nuclear Ki-67 protein (pKi-67), using nanotechnology-based
photodynamic therapy (PDT). Antibodies against pKi-67 are widely used as prognostic tools for
tumor diagnosis. In this work, anti pKi-67 antibodies were first conjugated to fluorescein
isothiocyanate (FITC) and then encapsulated inside liposomes. After incubation of OVCAR-5
ovarian cancer cells with these liposomes, confocal microscopy confirmed the localization of the
antibodies to the nucleoli of the cells. Irradiation with a 488 nm laser led to a significant loss of
cell viability. The specificity of this approach for pKi-67 positive cells was demonstrated in
confluent human lung fibroblasts (MRC-5) where only a small population of cells stain positive
for pKi-67 and only minimal cell death was observed. Taken together, our findings suggest that
pKi-67 targeted with nano-platform is an attractive therapeutic target in cancer therapy.
Pancreatic cancer (PanCa) has a poor prognosis with a 5-year survival rate of only 5%. Photodynamic therapy (PDT) has
shown promising results in treating PanCa. Mechanism-based combinations with PDT have enhanced treatment
outcome. Agents tested with PDT include Avastin, an antibody against vascular endothelial growth factor (VEGF) which
is approved for treating various cancers. Simultaneous delivery of drugs in nano-constructs could improve the treatment
response of mechanism based combination therapies. Here, we investigate the effect of neutralizing VEGF using
nanotechnology for the delivery of Avastin in combination with PDT. For this we used a construct called "nanocells" in
which the photosensitizer was trapped inside polymer nanoparticles and these, with Avastin, were then encapsulated
inside liposomes. In vitro, nanocells containing Avastin (NCA) significantly enhanced cytotoxicity in PanCa cells. NCA
based PDT also significantly improved treatment response in mice that were orthotopically implanted with PanCa.
Avastin delivered extracellularly in combination with PDT did not show any improvement. Here we propose a new
paradigm for Avastin-based therapy by combining intracellular delivery of the antibody and PDT using nanotechnology
for treating PanCa.
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