Biology subjects

Marinkovic, P.

Publications and source records attributed to Marinkovic, P..

3 recordsLinked to original sources

bioRxiv2025

The delivery of nano-formulated drugs to solid tumours is selectively increased by co-application of the vascular disrupting agent CA4P

Improving the efficacy of existing cytotoxic chemotherapeutics requires increasing drug delivery to tumours while minimising systemic toxicity. Formulating these drugs as nanoparticles can reduce their exposure to healthy tissues, but broadly applicable strategies to enhance tumoral accumulation are lacking. Here, we show that co-administering small molecule vascular disrupting agents together with nanoparticle formulations (e.g. diagnostic reporters, or clinical drugs irinotecan and doxorubicin) increases their tumoral uptake by up to threefold, without raising systemic exposure. In a syngeneic mouse model of triple-negative breast cancer, this enhancement diminished when co-treatments were repeated, limiting its therapeutic benefit. However, since most solid tumour types are susceptible to vascular disrupting agents, this approach may be a broadly applicable strategy to improve the selectivity of drug delivery: with particular relevance for single dose use in diagnostic or research settings. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/669501v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@a5b07corg.highwire.dtl.DTLVardef@1e5dcd2org.highwire.dtl.DTLVardef@49134org.highwire.dtl.DTLVardef@1d90aae_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

Alpha-synucleinopathies are characterized by self-aggregation of the protein alpha-synuclein (a-syn), causing alterations on the molecular and cellular level. To unravel the impact of transneuronal spreading and templated misfolding of a-syn on the microcircuitry of remotely connected brain areas, we investigated cortical neuron function in awake mice 9 months after a single intrastriatal injection of a-syn preformed fibrils (PFFs), using in vivo two-photon calcium imaging. We found altered function of layer 2/3 cortical neurons in somatosensory cortex (S1) of PFF-inoculated mice, as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important pathomechanism in alpha-synucleinopathies and demonstrate a clear association between the spread of toxic proteins and the initiation of altered neuronal function in remotely connected areas.

neuroscience↗

bioRxiv2019

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Alzheimers disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.\n\nO_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC=\"FIGDIR/small/801902v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (43K):\norg.highwire.dtl.DTLVardef@16f8461org.highwire.dtl.DTLVardef@5c0952org.highwire.dtl.DTLVardef@681c04org.highwire.dtl.DTLVardef@107854a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗