A suitable nanoparticle delivery system for 5-Aminolevulinic acidPhotodynamic therapy (ALA-PDT) for pancreatic ca
Progetto Pancreatic ductal adenocarcinoma represents one of the most severe
cancers, with extremely poor survival rate and it is a leading cause of cancer
death worldwide. Although in recent years several molecules having
anticancer activity have been identified in vitro, a very few of them showed
partial efficacy in clinical trials. This is partially due to the lack of an
adequate model suitable for drug testing, being the conventional cell cultures
ineffective in recapitulating the complex interactions among cells in the
pancreas microenvironment. In last years, three-dimensional cell cultures,
such as organoids and bioengineered organs-on-chips, are emerging as
crucial tools for research on several diseases. In particular, a human
Pancreas-on-a-Chip is able to provide a microenvironment that resembles
the human pathophysiological conditions more closely than existing in vitro
models.
Photodynamic therapy (PDT) is a form of non-ionizing radiation therapy that
uses a photosensitizer (Ps), combined with light to produce singlet oxygen,
thus exerting anti-cancer activity through apoptotic, necrotic, or autophagic
cancer cell death without exerting systemic adverse effects.
5-Aminolevulinic acid (5-ALA), showed anticancer activity in several
cancer cell types, and our preliminary experiment data have suggested that
5-ALA in poloxamer matrix (ALAD) in combination with PDT strongly
affects cell viability in a pancreatic cancer cell line. However, to the best of
our knowledge, only few works report about the use of silica-based materials
for 5-ALA storage and delivery, and in particular, no attempts have been
made yet to deliver it to pancreatic cancer. Since nanoparticles (NPs) have
been widely used in drug delivery for cancer therapy since they preferentially
accumulate and remain in tumors by several different mechanisms, they can
be exploited as 5-ALA nanocarriers.
Hence, in this project we propose a novel pH-sensitive drug delivery
system of mesoporous silica nanoparticles (MSNs) modified by
polydopamine (PDA) for controlled release of 5-ALA to pancreatic cancer
and to exploit the Emulate® organ-on-a-chip platform to model a human
pancreatic-cancer-on-a-chip composed of healthy, cancer, endothelial and
immune cells, and test the effects of 5-ALA activated by photodynamic
therapy (5-ALA-PDT) alone or incapsulated in nanoparticles. This model
will provide unprecedent preclinical in vitro tool for monitoring cancer
progression/regression and studying inflammation and immune cell
migration in pancreatic cancer microenvironment. In addition, the developed
hybrid nanoparticles will be tested in vivo experiments to validate it as an
efficient formulation suitable for oral and/or intravenous administration.