Crown-like structures (CLSs) are adipose microenvironments of macrophages engulfing adipocytes. Their histological density in visceral adipose tissue (VAT) predicts metabolic disorder progression in obesity and is believed to initiate obesity comorbidities. Here, we use three-dimensional (3D) light sheet microscopy and deep learning to quantify 3D features of VAT CLSs in lean and obese states. Obese CLS densities are significantly higher, composing 3.9% of tissue volume compared with 0.46% in lean tissue. Across the states, individual CLS structural characteristics span similar ranges; however, subpopulations are distinguishable. Obese VAT contains large CLSs absent from lean tissues, located near the tissue center, while lean CLSs have higher volumetric cell densities and prolate shapes. These features are consistent with inefficient adipocyte elimination in obesity that contributes to chronic inflammation, representing histological biomarkers to assess adipose pathogenesis. This tissue processing, imaging, and analysis pipeline can be applied to quantitatively classify 3D microenvironments across diverse tissues.
The development of effective therapeutic strategies for glioblastoma faces challenges such as modulating the blood brain barrier (BBB) for drug influx and selectively targeting tumor cells. Nanocarrier drug delivery strategies are functionalized to enhance vascular permeability. We engineered superparamagnetic iron oxide nanoparticle (SPION) based polymeric nanocomposites (84.37 ± 12.37 nm / 101.56 ± 7.42 nm) embedding temozolomide (TMZ) targeted against glioblastoma by tagging an antibody against nestin, a stem cell marker, and transferrin / polysorbate-80 to permeate the BBB. The targeting and therapeutic efficacy of the nanocomposite resulted in enhanced permeability across the BBB in an orthotopic glioblastoma xenograft model. Sustained release of TMZ from the nanocomposite contributed to enhanced tumor cell death while sparing normal brain cells as evidenced through micro SPECT/CT analysis. The functionalized nanocomposites showed significant reductions in tumor volume compared to pure TMZ, as substantiated by reduced proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67. We report here a novel targeted TMZ delivery strategy using a potent homing moiety, nestin, tagged to a polymeric nanocomposite to target glioblastoma. In addition to tumor targeting, this study constitutes a broad horizon for enhanced therapeutic efficacy with further scope for capitalizing on the magnetic properties of SPION for targeted killing of cancer cells while sparing normal tissues.
Background Glioblastoma, or glioblastoma multiforme (GBM), remains a fatal cancer type despite the remarkable progress in understanding the genesis and propagation of the tumor. Current treatment modalities, comprising mainly of surgery followed by adjuvant chemoradiation, are insufficient for improving patients' survival owing to existing hurdles, including the blood–brain barrier (BBB). In contemporary practice, the prospect of long-term survival or cure continues to be a challenge for patients suffering from GBM. This review provides an insight into the drug delivery strategies and the significant efforts made in lipid-based nanoplatform research to circumvent the challenges in optimal drug delivery in GBM. Area covered Owing to the unique properties of lipid-based nanoplatforms and advancements in clinical translation, this article describes the application of various stimuli-responsive lipid nanocarriers and tumor subcellular organelle-targeted therapy to give an idea about the strategies that can be applied to enhance site-specific drug delivery for GBM. Furthermore, active targeting of drugs via surface-modified lipid-based nanostructures and recent findings in alternative therapeutic platforms such as gene therapy, immunotherapy, and multimodal therapy have also been overviewed. Expert opinion Lipid-based nanoparticles stand out among the other nanocarriers explored for GBM drug delivery, as they support both passive and active drug targeting by crossing/bypassing the BBB at the same time minimizing toxicity and projects better pharmacological parameters. Although these nanocarriers could be a plausible choice for treating GBM, in-depth research is essential to advance neuro-oncology research and enhance outcomes in patients with brain tumors.
Macrophages are white blood cells with diverse functions contributing to a healthy immune response as well as the pathogenesis of cancer, osteoarthritis, atherosclerosis, and obesity. Due to their pleiotropic and dynamic nature, tools for imaging and tracking these cells at scales spanning the whole body down to microns could help to understand their role in disease states. Here we report fluorescent and radioisotopic quantum dots (QDs) for multimodal imaging of macrophage cells in vivo, ex vivo, and in situ. Macrophage specificity is imparted by click-conjugation to dextran, a biocompatible polysaccharide that natively targets these cell types. The emission spectral band of the crystalline semiconductor core was tuned to the near-infrared for optical imaging deep in tissue, and probes were covalently conjugated to radioactive iodine for nuclear imaging. The performance of these probes was compared with all-organic dextran probe analogues in terms of their capacity to target macrophages in visceral adipose tissue using in vivo positron emission tomography/computed tomography (PET/CT) imaging, in vivo fluorescence imaging, ex vivo fluorescence, post-mortem isotopic analyses, and optical microscopy. All probe classes exhibited equivalent physicochemical characteristics in aqueous solution and similar in vivo targeting specificity. However, dextran-mimetic QDs provided enhanced signal-to-noise ratio for improved optical quantification, long-term photostability, and resistance to chemical fixation. In addition, the vascular circulation time for the QD-based probes was extended 9-fold compared with dextran, likely due to differences in conformational flexibility. The enhanced photophysical and photochemical properties of dextran-mimetic QDs may accelerate applications in macrophage targeting, tracking, and imaging across broad resolution scales, particularly advancing capabilities in single-cell and single-molecule imaging and quantification.
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