Primary Human Breast Cancer-Associated Endothelial Cells Favor Interactions with Nanomedicines.

Cancer nanomedicines predominately rely on transport processes controlled by tumor-associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer-associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super-resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor-associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor-associated endothelial cell-mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines.

Toward the Scalable, Rapid, Reproducible, and Cost-Effective Synthesis of Personalized Nanomedicines at the Point of Care.

Organic nanoparticles are used in nanomedicine, including for cancer treatment and some types of COVID-19 vaccines. Here, we demonstrate the scalable, rapid, reproducible, and cost-effective synthesis of three model organic nanoparticle formulations relevant to nanomedicine applications. We employed a custom-made, low-cost fluid mixer device constructed from a commercially available three-dimensional printer. We investigated how systematically changing aqueous and organic volumetric flow rate ratios determined liposome, polymer nanoparticle, and solid lipid nanoparticle sizes, size distributions, and payload encapsulation efficiencies. By manipulating inlet volumes, we synthesized organic nanoparticles with encapsulation efficiencies approaching 100% for RNA-based payloads. The synthesized organic nanoparticles were safe and effective at the cell culture level, as demonstrated by various assays. Such cost-effective synthesis approaches could potentially increase the accessibility to clinically relevant organic nanoparticle formulations for personalized nanomedicine applications at the point of care, especially in nonhospital and low-resource settings.

Gold Nanoparticles Disrupt the IGFBP2/mTOR/PTEN Axis to Inhibit Ovarian Cancer Growth.

By exploiting the self-therapeutic properties of gold nanoparticles (GNPs) a molecular axis that promotes the growth of high-grade serous ovarian cancer (HGSOC), one of the deadliest gynecologic malignancies with poorly understood underlying molecular mechanisms, has been identified. The biodistribution and toxicity of GNPs administered by intravenous or intraperitoneal injection, both as a single dose or by repeated dosing over two weeks are first assessed; no biochemical or histological toxicity to vital organs is found. Using an orthotopic patient-derived xenograft (PDX) model of HGSOC, the authors then show that GNP treatment robustly inhibits tumor growth. Investigating the molecular mechanisms underlying the GNP efficacy reveals that GNPs downregulate insulin growth factor binding protein 2 (IGFBP2) by disrupting its autoregulation via the IGFBP2/mTOR/PTEN axis. This mechanism is validated by treating a cell line-based human xenograft tumor with GNPs and an mTOR dual-kinase inhibitor (PI-103), either individually or in combination with GNPs; GNP and PI-103 combination therapy inhibit ovarian tumor growth similarly to GNPs alone. This report illustrates how the self-therapeutic properties of GNPs can be exploited as a discovery tool to identify a critical signaling axis responsible for poor prognosis in ovarian cancer and provides an opportunity to interrogate the axis to improve patient outcomes.

Strategies for Delivering Nanoparticles across Tumor Blood Vessels.

Nanoparticle transport across tumor blood vessels is a key step in nanoparticle delivery to solid tumors. However, the specific pathways and mechanisms of this nanoparticle delivery process are not fully understood. Here, the biological and physical characteristics of the tumor vasculature and the tumor microenvironment are explored and how these features affect nanoparticle transport across tumor blood vessels is discussed. The biological and physical methods to deliver nanoparticles into tumors are reviewed and paracellular and transcellular nanoparticle transport pathways are explored. Understanding the underlying pathways and mechanisms of nanoparticle tumor delivery will inform the engineering of safer and more effective nanomedicines for clinical translation.