Mondal, Sujan Kumar

Abstract Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non‐viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein‐4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem‐like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti‐glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti‐proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient‐derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

AbstractBrain cancer persists as a difficult‐to‐treat condition. In particular, metastatic brain cancer and malignant primary brain tumors such as glioblastoma (GBM) are among the most deadly and still carry a dismal prognosis despite current standard of care with surgery and chemo‐radiation. Recent advances in nanotechnology have led to innovative nanomedicine strategies for the treatment of brain cancers and specifically for GBM. These strategies represent promising alternative or adjunctive therapies for conventional treatment modalities and are increasingly designed to target specific cell types such as brain tumor‐initiating cells and immune cells. This review provides an update on emerging insights into these nanomedicine strategies with a focus on nanoparticles as tools that facilitate 1) drug delivery 2) gene therapy, and 3) engineered‐cellular therapy for GBM and future directions for brain cancer treatment.

AbstractA lipid‐conjugated, estrogenic derivative molecule, ESC8, compared with other estrogenic molecules, encourages cell death in both ER‐positive and ER‐negative breast cancer cells. A rapid and highly sensitive assay method has been developed and validated for the estimation of a ESC8 in rat plasma using liquid chromatography coupled with mass spectrometry under positive‐ion mode with electrospray ionization. The sample process includes using methanol for precipitation of ESC8 and dextromethorphan (internal standard, IS) from plasma. Chromatographic separation was achieved with methanol–water–formic acid (70:30:0.1% v/v/v) pumped at a flow rate of 0.3mL/min and a C18 column (50 × 2.1 mm i.d., 1.7 μm particle size) with a total run time of 5 min. The m/z ions monitored were 568.5 and 272.1 for ESC8 and IS, respectively. The lower limit of quantitation achieved was 1.08 ng/mL and linearity was observed from 5 to 500 ng/mL. The intra‐ and inter‐day precisions were <4%. The proposed method was successfully applied to a preliminary pharmacokinetic study of ESC8 liposomal formulation following an intraperitoneal administration of 3.67 mg/kg in rats. The concentrations of ESC8 in plasma were quantifiable up to 36 h. The peak concentration of ESC8 was found to be 110.72 ng/mL, the area under the concentration–time curve was 1625.23ng/mL h and the half‐life was 11.72 h.