Reactive acid anhydride coated carbon nanodots perpared by water-free thermolysis of citric acid are a gateway for engineering clicked (bio)nanoconstucts.
Lack of efficacy and a low overall success rate of phase I-II clinical trials are the most common failures when it comes to advancing cancer treatment. Current drug sensitivity screenings present several challenges including differences in cell growth rates, the inconsistent use of drug metrics, and the lack of translatability. Here, we present a patient-derived 3D culture model to overcome these limitations in breast cancer (BCa). The human plasma-derived 3D culture model (HuP3D) utilizes patient plasma as the matrix, where BCa cell lines and primary BCa biopsies were grown and screened for drug treatments. Several drug metrics were evaluated from relative cell count and growth rate curves. Correlations between HuP3D metrics, established preclinical models, and clinical effective concentrations in patients were determined. HuP3D efficiently supported the growth and expansion of BCa cell lines and primary breast cancer tumors as both organoids and single cells. Significant and strong correlations between clinical effective concentrations in patients were found for eight out of ten metrics for HuP3D, while a very poor positive correlation and a moderate correlation was found for 2D models and other 3D models, respectively. HuP3D is a feasible and efficacious platform for supporting the growth and expansion of BCa, allowing high-throughput drug screening and predicting clinically effective therapies better than current preclinical models.
Water-insoluble carbon dots are recognized as promising materials, although their applications in nanomedicine are rarely explored, despite their lipophilic character and foreseen compatibility with biological membranes. In this article, we...
Bisphosphonates (BPs) are bone-binding
molecules that provide targeting
capabilities to bone cancer cells when conjugated with drug-carrying
polymers. This work reports the design, synthesis, and biological
evaluation of polyethyleneimine–BP–cyclodextrin (PEI-BP-CD)
ternary conjugates with supramolecular capabilities for the loading
of antineoplastic drugs. A straightforward, modular, and versatile
strategy based on the click aza-Michael addition reaction of vinyl
sulfones (VSs) allows the grafting of BPs targeting ligands and βCD
carrier appendages to the PEI polymeric scaffold. The
in vitro
evaluation (cytotoxicity, cellular uptake, internalization routes,
and subcellular distribution) for the ternary conjugates and their
doxorubicin inclusion complexes in different bone-related cancer cell
lines (MC3T3-E1 osteoblasts, MG-63 sarcoma cells, and MDA-MB-231 breast
cancer cells) confirmed specificity, mitochondrial targeting, and
overall capability to mediate a targeted drug transport to those cells.
The
in vivo
evaluation using xenografts of MG-63
and MDA-MB-231 cells on mice also confirmed the targeting of the conjugates.
Magnetite nanoparticles (MNPs) coated by branched poly (ethylene-imine) (PEI) were synthesized in a one-pot. Three molecular weights of PEI were tested, namely, 1.8 kDa (sample MNP-1), 10 kDa (sample MNP-2), and 25 kDa (sample MNP-3). The MNP-1 particles were further functionalized with folic acid (FA) (sample MNP-4). The four types of particles were found to behave magnetically as superparamagnetic, with MNP-1 showing the highest magnetization saturation. The particles were evaluated as possible hyperthermia agents by subjecting them to magnetic fields of 12 kA/m strength and frequencies ranging between 115 and 175 kHz. MNP-1 released the maximum heating power, reaching 330 W/g at the highest frequency, in the high side of reported values for spherical MNPs. In vitro cell viability assays of MNP-1 and MNP-4 against three cell lines expressing different levels of FA receptors (FR), namely, HEK (low expression), and HeLa (high expression), and HepG2 (high expression), demonstrated that they are not cytotoxic. When the cells were incubated in the presence of a 175 kHz magnetic field, a significant reduction in cell viability and clone formation was obtained for the high expressing FR cells incubated with MNP-4, suggesting that MNP-4 particles are good candidates for magnetic field hyperthermia and active targeting.
This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.
A modular platform for targeted delivery was based on a single chain variable (ScFv) fragment fused to maltose-binding protein (MBP). Using different maltosylated ligands it is likely to target, transport drugs, or deliver genes to specific cells.
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