Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.
Rapid intracellular degradation of
current drug-delivery nanocarriers
presents a challenge for achieving ideal controlled drug-release kinetics.
Recent in vivo studies have shown that porous hybrid metal-organic
frameworks (MOFs), belonging to the Materials of Institute Lavoisier
(MIL) family, display prolonged biodegradation behavior. In this study,
we investigated stability of these materials in Kupffer cells, a relevant
target for the treatment of several life-threatening immune-mediated
liver diseases. For this aim, we selected fluorescently labeled microporous
MOF particles of MIL88A and MIL88B-NH2, built from trimers
of Fe(III) octahedra, as an inorganic component, and fumarate (MIL88A)
or 2-amino terephthalate (MIL88B-NH2), as an organic linker.
Cell uptake inhibition analysis of MOF particles by a Kupffer cell
line (KUP5) has shown that phagocytosis is the major endocytic pathway
involved in MIL88B-NH2 internalization. Investigation of
MOF interaction with KUP5 cells by real-time microscopy indicated
that the structure of MIL88B-NH2 MOFs stays intact up to
15 min after uptake, followed by MOF accumulation in acidic cell compartments
and slow degradation, reaching a minimum of 10–15% decomposition
over 24 h. MIL88A particles demonstrated similar degradation kinetics.
Analysis of the mechanisms of MOF degradation has shown that inhibition
of phagosome acidification as well as protease activity does not prevent
decomposition of MIL88B-NH2 particles. Thus, our study
demonstrates the relative stability of the MOF structure in the phagolysosomal
environment of Kupffer cells, revealing potential use of these materials
for controlled drug delivery in a case of immune-mediated liver diseases.
Robust deposition of extracellular
matrix is a significant barrier
for delivery of nanotherapeutics and small-molecule anticancer drugs
to different tumors including pancreatic ductal adenocarcinoma. Here,
we investigated permeation and total uptake of polystyrene nanoparticles
of different diameters in 3D multicellular spheroid models of pancreatic
tumors. Special attention was given to analysis of the impact of endocytic
processes on nanoparticle accumulation and distribution in spheroids.
We generated spheroids of BxPC3 or PANC-1 cells that were able to
internalize 20, 100, and 500 nm fluorescent polystyrene beads with
different efficacies, resulting in 20 ≫100 > 500 nm and
100
> 500 > 20 nm trends, respectively. It was found that endocytosis
and transcytosis increased overall nanoparticle uptake and facilitated
permeation of 20 nm beads in BxPC3 spheroids, whereas 100 and 500
nm particles did not penetrate. In PANC-1 spheroids, penetration of
nanoparticles also decreased with the increase of size but was not
significantly affected by endocytic processes. Thus, our study showed
that passive diffusion and endocytic processes may have a different
contribution to nanoparticle accumulation and distribution in spheroid
models of pancreatic cancer.
ESRI has been shown to be a new and completely noninvasive method to monitor microacidity in different skin layers and on the skin surface. This nondestructive method allows serial measurements on skin samples to be performed without any preparatory steps.
We have used transmission electron microscopy and optical microscopy to examine the effect that grain size and heat treatment have on twinning and microcracking in polycrystalline Y1Ba2Cu307_8. It is shown that isothermal oxygenation heat treatments produce twin structures consisting of parallel twins, with a characteristic spacing that increases with increasing grain size. Slow cooling through the temperature range where the orthorhombic-to-tetragonal transformation induces twinning, however, produces a structure consisting of a hierarchical arrangement of intersecting twins, the scale of which appears to be independent of grain size. It is also shown that the microcracking induced by anisotropic changes in grain dimensions on cooling or during oxygenation can be suppressed if the grain size of the material is kept below about 1 fim. The results are examined in the light of current models for transformation twinning and microcracking and the models used to access the effect other processing variables such as oxygen content, doping or heat treatment may have on the microstructure of Y1Ba2Cu307_8.
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