As2O3 was introduced as an anion into MOF nanoparticles via a postsynthetic ligand exchange; material cytotoxicity was investigated in vitro.

Despite having a rich history as a poison, arsenic and its compounds have also gained a great reputation as promising anticancer drugs. As a pioneer, arsenic trioxide has been approved for the treatment of acute promyelocytic leukemia. Many in vitro studies suggested that arsenic trioxide could also be used in the treatment of solid tumors. However, the transition from bench to bedside turned out to be challenging, especially in terms of the drug bioavailability and concentration reaching tumor tissues. To address these issues, nanomedicine tools have been proposed. As nanocarriers of arsenic trioxide, various materials have been examined including liposomes, polymer, and inorganic nanoparticles, and many other materials. This review gives an overview of the existing strategies of delivery of arsenic trioxide in cancer treatment with a focus on the drug encapsulation approaches and medicinal impact in the treatment of solid tumors. It focuses on the progress in the last years and gives an outlook and suggestions for further improvements including theragnostic approaches and targeted delivery.

For exact molecular diagnosis of CNS tumors, tumor tissue obtained through surgery is usually needed. However, knowledge on the molecular tumor type beforehand might influence surgical strategies and reduce surgery-associated risks. Molecular analyses of liquid biopsies have therefore gained increasing interest in order to secure diagnosis before surgery or to replace surgery in rare instances. Moreover, the minimally invasive nature of liquid biopsies enables a tight and longitudinal tumor monitoring with potentially higher sensitivity than imaging approaches. In this study, we applied Nanopore sequencing to 129 cell-free DNA (cfDNA) samples from the cerebrospinal fluid (CSF) of brain tumor patients, with 70.5% coming from pediatric patients. We analyzed copy number variations (CNV) and methylation patterns with a recently published random forest classifier (NanoDx). Circulating tumor DNA (ctDNA) was detected and successfully classified the tumor in 45% of all technically successful samples, both in pre- and early post-surgery samples as well as in samples from >14 days post-surgery, often with clinically unclear residual tumor or disease relapse. In all samples containing detectable tumor DNA, CNV analysis was more frequently successful than methylation analysis with overall detection rates of 88% and 44%, respectively. CNV analysis revealed diagnostic alterations, such as C19MC amplifications in ETMR as well as Chr.1q gain and Chr.6q loss in PFA ependymoma, which are important prognostic markers. Methylation analysis also allowed the classification of tumors with balanced genomes, like craniopharyngiomas. Finally, we were able to perform longitudinal analyses and found aberrations in the CNV profiles that were private to the tumor relapse, highlighting the potential of liquid biopsies to detect potentially relevant changes of tumor biology. Our results show that Nanopore sequencing is a promising approach to establish initial tumor diagnosis and to monitor disease courses by lumbar punctures.

Atypical Teratoid Rhabdoid Tumors (ATRT) are aggressive brain malignancies of the infant. Despite intensive multimodal therapy, the overall prognosis remains poor, making investigations on targeted therapies crucial. Arsenic trioxide (ATO) is known to inhibit cell growth of ATRT in vitro and in vivo but its efficacy in solid tumors is limited by its adverse effects. We aimed to characterize whether a nanoparticle-based drug delivery could overcome these limitations. Therefore metal-organic frameworks containing ATO (MOF-ATO) were constructed. To improve drug specificity further, we searched for unique proteins on the surface of ATRT, in order to create antibody-drug-conjugates out of MOF-ATO and an ATRT-specific ligand. ATRT are marked by a biallelic loss of SMARCB1, which results in an activation of the repressive histone methyltransferase EZH2. After chemical inhibition of EZH2 with GSK126, a mass spectrometric based screening for differentially expressed surface proteins was performed. Treatment with ATO, as well as MOF-ATO and GSK126 each reduces the cell viability of ATRT cell lines. It results in a cell cycle arrest and an induction in apoptosis, being analysed via MTT test and flow cytometry. GSK126 treatment causes a significant upregulation of several cell surface proteins, upon them the Lymphocyte antigen 6 family member D (LY6D). Being rarely expressed on other human cells, this protein is an interesting candidate. An antibody-drug-conjugate consisting of MOF-ATO and LY6D-ligands could be a promising approach for future targeted therapies of ATRT.