Upconversion nanoparticles (UCNPs)
coated with polyethylenimine
(PEI) are popular background-free optical contrast probes and efficient
drug and gene delivery agents attracting attention in science, industry,
and medicine. Their unique optical properties are especially useful
for subsurface nanotheranostics applications, in particular, in skin.
However, high cytotoxicity of PEI limits safe use of UCNP@PEI, and
this represents a major barrier for clinical translation of UCNP@PEI-based
technologies. Our study aims to address this problem by exploring
additional surface modifications to UCNP@PEI to create less toxic
and functional nanotheranostic materials. We designed and synthesized
six types of layered polymer coatings that envelop the original UCNP@PEI
surface, five of which reduced the cytotoxicity to human skin keratinocytes
under acute (24 h) and subacute (120 h) exposure. In parallel, we
examined the photoluminescence spectra and lifetime of the surface-modified
UCNP@PEI. To quantify their brightness, we developed original methodology
to precisely measure the colloidal concentration to normalize the
photoluminescence signal using a nondigesting mass spectrometry protocol.
Our results, specified for the individual coatings, show that, despite
decreasing the cytotoxicity, the external polymer coatings of UCNP@PEI
quench the upconversion photoluminescence in biologically relevant
aqueous environments. This trade-off between cytotoxicity and brightness
for surface-coated UCNPs emphasizes the need for the combined assessment
of the viability of normal cells exposed to the nanoparticles and
the photophysical properties of postmodification UCNPs. We present
an optimized methodology for rational surface design of UCNP@PEI in
biologically relevant conditions, which is essential to facilitate
the translation of such nanoparticles to the clinical applications.
The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, immune and stromal cells, and adjacent non-tumorous tissue, contributes to cancer pathogenesis. Thus, TME-derived biomarkers have many clinical applications. This review is predominately based on the most recent publications (manuscripts published in a last 5 years, or seminal publications published earlier) and fills a gap in the current literature on the cancer biomarkers derived from the TME, with particular attention given to the ECM and products of its processing and degradation, ECM-associated extracellular vesicles (EVs), biomechanical characteristics of ECM, and ECM-derived biomarkers predicting response to the immunotherapy. We discuss the clinical utility of the TME-incorporating three-dimensional in vitro and ex vivo cell culture models for personalized therapy. We conclude that ECM is a critical driver of malignancies and ECM-derived biomarkers should be included in diagnostics and prognostics panels of markers in the clinic.
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