Esophageal Granular Cell Tumor: An Uncommon Cause of Dysphagia.

Granular cell tumors (GCTs) are rare, typically benign, solitary neoplasms that can arise throughout the body, with reports of cases in the tongue, esophagus, colon, skin, vulva, and skeletal muscle, among others. Although GCTs are usually asymptomatic, esophageal GCTs can grow large enough to cause dysphagia. When developing the differential diagnosis for dysphagia, a broad consideration includes routine etiologies such as esophageal strictures, eosinophilic esophagitis, carcinoma, webs and rings, achalasia, and motility disorders, but GCTs may not readily come to mind. Due to their scarcity, this case report is presented to raise awareness of esophageal GCTs and emphasize key goals for diagnosing and managing this uncommon yet treatable cause of dysphagia. This case report details the clinical course of a patient presenting with a chief complaint of difficulty swallowing that was found to be caused by a subepithelial esophageal tumor discovered with esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS). Histopathological studies paired with immunohistochemical investigations of a tissue biopsy confirmed the etiology of the offending esophageal mass to be a GCT. The patient's dysphagia resolved after endoscopic mucosal resection of the GCT, and follow-up evaluations have remained negative for recurrence. This case highlights the esophageal GCT as an uncommon source of dysphagia and the need for EGD and EUS evaluations of subepithelial esophageal lesions accompanied by histopathological analysis for a definitive diagnosis of GCT.

High-Throughput Dispensing of Viscous Solutions for Biomedical Applications.

Cells cultured in three-dimensional scaffolds express a phenotype closer to in vivo cells than cells cultured in two-dimensional containers. Natural polymers are suitable materials to make three-dimensional scaffolds to develop disease models for high-throughput drug screening owing to their excellent biocompatibility. However, natural polymer solutions have a range of viscosities, and none of the currently available liquid dispensers are capable of dispensing highly viscous polymer solutions. Here, we report the development of an automated scaffold dispensing system for rapid, reliable, and homogeneous creation of scaffolds in well-plate formats. We employ computer-controlled solenoid valves to regulate air pressure impinging upon a syringe barrel filled with scaffold solution to be dispensed. Automated dispensing of scaffold solution is achieved via a programmable software interface that coordinates solution extrusion and the movement of a dispensing head. We show that our pneumatically actuated dispensing system can evenly distribute high-viscosity, chitosan-based polymer solutions into 96- and 384-well plates to yield highly uniform three-dimensional scaffolds after lyophilization. We provide a proof-of-concept demonstration of high-throughput drug screening by culturing glioblastoma cells in scaffolds and exposing them to temozolomide. This work introduces a device that can hasten the creation of three-dimensional cell scaffolds and their application to high-throughput testing.

Inorganic Nanomaterial-Mediated Gene Therapy in Combination with Other Antitumor Treatment Modalities.

Cancer is a genetic disease originating from the accumulation of gene mutations in a cellular subpopulation. Although many therapeutic approaches have been developed to treat cancer, recent studies have revealed an irrefutable challenge that tumors evolve defenses against some therapies. Gene therapy may prove to be the ultimate panacea for cancer by correcting the fundamental genetic errors in tumors. The engineering of nanoscale inorganic carriers of cancer therapeutics has shown promising results in the efficacious and safe delivery of nucleic acids to treat oncological diseases in small-animal models. When these nanocarriers are used for co-delivery of gene therapeutics along with auxiliary treatments, the synergistic combination of therapies often leads to an amplified health benefit. In this review, an overview of the inorganic nanomaterials developed for combinatorial therapies of gene and other treatment modalities is presented. First, the main principles of using nucleic acids as therapeutics, inorganic nanocarriers for medical applications and delivery of gene/drug payloads are introduced. Next, the utility of recently developed inorganic nanomaterials in different combinations of gene therapy with each of chemo, immune, hyperthermal, and radio therapy is examined. Finally, current challenges in the clinical translation of inorganic nanomaterial-mediated therapies are presented and outlooks for the field are provided.

Iron oxide nanoparticles for immune cell labeling and cancer immunotherapy.

Cancer immunotherapy is a novel approach to cancer treatment that leverages components of the immune system as opposed to chemotherapeutics or radiation. Cell migration is an integral process in a therapeutic immune response, and the ability to track and image the migration of immune cells in vivo allows for better characterization of the disease and monitoring of the therapeutic outcomes. Iron oxide nanoparticles (IONPs) are promising candidates for use in immunotherapy as they are biocompatible, have flexible surface chemistry, and display magnetic properties that may be used in contrast-enhanced magnetic resonance imaging (MRI). In this review, advances in application of IONPs in cell tracking and cancer immunotherapy are presented. Following a brief overview of the cancer immunity cycle, developments in labeling and tracking various immune cells using IONPs are highlighted. We also discuss factors that influence the effectiveness of IONPs as MRI contrast agents. Finally, we outline different approaches for cancer immunotherapy and highlight current efforts that utilize IONPs to stimulate immune cells to enhance their activity and response to cancer.

Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer.

Triple negative breast cancer is difficult to treat effectively, due to its aggressiveness, drug resistance, and lack of the receptors required for hormonal therapy, particularly at the metastatic stage. Here, we report the development and evaluation of a multifunctional nanoparticle formulation containing an iron oxide core that can deliver doxorubicin, a cytotoxic agent, and polyinosinic:polycytidylic acid (Poly IC), a TLR3 agonist, in a targeted and simultaneous fashion to both breast cancer and dendritic cells. Endoglin-binding peptide (EBP) is used to target both TNBC cells and vasculature epithelia. The nanoparticle demonstrates favorable physicochemical properties and a tumor-specific targeting profile. The nanoparticle induces tumor apoptosis through multiple mechanisms including direct tumor cell killing, dendritic cell-initiated innate and T cell-mediated adaptive immune responses. The nanoparticle markedly inhibits tumor growth and metastasis and substantially extends survival in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer (TNBC). This study points to a promising platform that may substantially improve the therapeutic efficacy for treating metastatic TNBC.

Graphene Quantum Dots and Their Applications in Bioimaging, Biosensing, and Therapy.

Graphene quantum dots (GQDs) are carbon-based, nanoscale particles that exhibit excellent chemical, physical, and biological properties that allow them to excel in a wide range of applications in nanomedicine. The unique electronic structure of GQDs confers functional attributes onto these nanomaterials such as strong and tunable photoluminescence for use in fluorescence bioimaging and biosensing, a high loading capacity of aromatic compounds for small-molecule drug delivery, and the ability to absorb incident radiation for use in the cancer-killing techniques of photothermal and photodynamic therapy. Recent advances in the development of GQDs as novel, multifunctional biomaterials are presented with a focus on their physicochemical, electronic, magnetic, and biological properties, along with a discussion of technical progress in the synthesis of GQDs. Progress toward the application of GQDs in bioimaging, biosensing, and therapy is reviewed, along with a discussion of the current limitations and future directions of this exciting material.

Microfluidic Synthesis of Iron Oxide Nanoparticles.

Research efforts into the production and application of iron oxide nanoparticles (IONPs) in recent decades have shown IONPs to be promising for a range of biomedical applications. Many synthesis techniques have been developed to produce high-quality IONPs that are safe for in vivo environments while also being able to perform useful biological functions. Among them, coprecipitation is the most commonly used method but has several limitations such as polydisperse IONPs, long synthesis times, and batch-to-batch variations. Recent efforts at addressing these limitations have led to the development of microfluidic devices that can make IONPs of much-improved quality. Here, we review recent advances in the development of microfluidic devices for the synthesis of IONPs by coprecipitation. We discuss the main architectures used in microfluidic device design and highlight the most prominent manufacturing methods and materials used to construct these microfluidic devices. Finally, we discuss the benefits that microfluidics can offer to the coprecipitation synthesis process including the ability to better control various synthesis parameters and produce IONPs with high production rates.

Nitrogen and Boron Dual-Doped Graphene Quantum Dots for Near-Infrared Second Window Imaging and Photothermal Therapy.

Fluorescence imaging of biological systems in the second near-infrared window (NIR-II) has recently drawn much attention because of its negligible background noise of autofluorescence and low tissue scattering. Here we present a new NIR-II fluorescent agent, graphene quantum dots dual-doped with both nitrogen and boron (N-B-GQDs). N-B-GQDs have an ultra-small size (~ 5 nm), are highly stable in serum, and demonstrate a peak fluorescent emission at 1000 nm and high photostability. In addition to the NIR-II imaging capability, N-B-GQDs efficiently absorb and convert NIR light into heat when irradiated by an external NIR source, demonstrating a photothermal therapeutic effect that kills cancer cells in vitro and completely suppresses tumor growth in a glioma xenograft mouse model. N-B-GQDs demonstrate a safe profile, prolonged blood half-life, and rapid excretion in mice, which are the characteristics favorable for in vivo biomedical applications.

A Portable Electrospinner for Nanofiber Synthesis and Its Application for Cosmetic Treatment of Alopecia.

A portable, handheld electrospinning apparatus is designed and constructed using off-the-shelf components and 3D-printed parts. The portable electrospinner is used to generate nanofibers with diameters ranging from 85 to 600 nm; examination of these fibers is achieved with scanning electron microscopy. This portable electrospinner has similar capabilities to standard stationary benchtop electrospinners in terms of the diversity of polymers the device is able to spin into nanofibers and their resulting size and morphology. However, it provides much more ambulatory flexibility, employs current-limiting measures that allow for safer operation and is cost effective. As a demonstration of the device's unique application space afforded by its portability, the device is applied in direct-to-skin electrospinning to improve the aesthetics of simulated hair loss in a mouse model by electrospinning dyed polyacrylonitrile nanofibers that mimic hair. The superficial nanofiber treatment for thinning hair is able to achieve an improvement in appearance similar to that of a commercially available powder product but outperforms the powder in the nanofiber's superior adherence to the affected area. The portable electrospinning apparatus overcomes many limitations of immobile benchtop electrospinners and holds promise for applications in consumer end-use scenarios such as the treatment of alopecia via cosmetic hair thickening.

Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model.

Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. SIGNIFICANCE: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.

Theranostic Nanoparticles for RNA-Based Cancer Treatment.

Certain genetic mutations lead to the development of cancer through unchecked cell growth and division. Cancer is typically treated through surgical resection, radiotherapy, and small-molecule chemotherapy. A relatively recent approach to cancer therapy involves the use of a natural process wherein small RNA molecules regulate gene expression in a pathway known as RNA interference (RNAi). RNA oligomers pair with a network of proteins to form an RNA-induced silencing complex, which inhibits the translation of mRNA into proteins, thereby controlling the expression of gene products. Synthetically produced RNA oligomers may be designed to target and silence specific oncogenes to provide cancer therapy. The primary challenges facing the use of the RNAi pathway for cancer therapy are the safe and efficacious delivery of RNA payloads and their release at pertinent sites within disease-causing cells. Nucleases are abundant in the bloodstream and intracellular environment, and therapeutic RNA sequences often require a suitable carrier to provide protection from degradation prior to reaching their site of action in the body. The use of metal core nanoparticles (NPs) serving as targeted delivery vehicles able to shield and direct RNA payloads to their intended destinations have recently gained favor. Biological barriers present in the body establish a size prerequisite for drug delivery vehicles; to overcome recognition by the body's immune system and to gain access to intracellular environments, drug carriers must be small (< 100 nm). Iron oxide and gold core NPs can be synthesized with a high degree of control to create uniform ultrasmall drug delivery vehicles capable of bypassing key biological barriers. While progress is being made in size control of liposomal and polymer NPs, such advances still lag in comparison to the exquisite tunability and time stability of size engineering achievable with metal core NPs at bulk scales. Further, unlike lipid- and viral-based transfection agents, the biodistribution of metal core NPs can be traced using noninvasive imaging techniques that capitalize on the interaction of electromagnetic radiation and the inorganic atoms at the core of the NPs. Finally, metal core NPs have been shown to match the transfection efficiency of conventional RNA-delivery vehicles while also providing less immunogenicity and minimal side effects through the addition of tumor-targeting ligands on their surface. This Account reviews recent advances in the use of iron oxide and gold NPs for RNAi therapy. An overview of the different types of RNA-based therapies is provided along with a discussion of the advantages and current limitations of the technique. We highlight design considerations for the use of iron oxide and gold NP carriers in RNAi, including a discussion of the importance of size and its role in traversing biological barriers, NP surface modifications required for targeted delivery and RNA payload release, and auxiliary properties supporting imaging functionality for treatment monitoring. Applications of NPs for combination therapies including the pairing of RNAi with chemotherapy, photothermal therapy, immunotherapy, and radiotherapy are explored through examples. Finally, future perspectives are provided with a focus on the current limitations and the potential for clinical translation of iron oxide and gold NPs in RNAi therapy.

Nanoparticle Biokinetics in Mice and Nonhuman Primates.

Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid, and cost-effective for tracking NPs noninvasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations.

Magnetite nanoparticles for cancer diagnosis, treatment, and treatment monitoring: recent advances.

The development of nanoparticles (NPs) for use in all facets of oncological disease detection and therapy has shown great progress over the past two decades. NPs have been tailored for use as contrast enhancement agents for imaging, drug delivery vehicles, and most recently as a therapeutic component in initiating tumor cell death in magnetic and photonic ablation therapies. Of the many possible core constituents of NPs, such as gold, silver, carbon nanotubes, fullerenes, manganese oxide, lipids, micelles, etc., iron oxide (or magnetite) based NPs have been extensively investigated due to their excellent superparamagnetic, biocompatible, and biodegradable properties. This review addresses recent applications of magnetite NPs in diagnosis, treatment, and treatment monitoring of cancer. Finally, some views will be discussed concerning the toxicity and clinical translation of iron oxide NPs and the future outlook of NP development to facilitate multiple therapies in a single formulation for cancer theranostics.

Approach to Rapid Synthesis and Functionalization of Iron Oxide Nanoparticles for High Gene Transfection.

Surface functionalization of theranostic nanoparticles (NPs) typically relies on lengthy, aqueous postsynthesis labeling chemistries that have limited ability to fine-tune surface properties and can lead to NP heterogeneity. The need for a rapid, simple synthesis approach that can provide great control over the display of functional moieties on NP surfaces has led to increased use of highly selective bioorthoganol chemistries including metal-affinity coordination. Here we report a simple approach for rapid production of a superparamagnetic iron oxide NPs (SPIONs) with tunable functionality and high reproducibility under aqueous conditions. We utilize the high affinity complex formed between catechol and Fe((III)) as a means to dock well-defined catechol modified polymer modules on the surface of SPIONs during sonochemical coprecipitation synthesis. Polymer modules consisted of chitosan and poly(ethylene glycol) (PEG) copolymer (CP) modified with catechol (CCP), and CCP functionalized with cationic polyethylenimine (CCP-PEI) to facilitate binding and delivery of DNA for gene therapy. This rapid synthesis/functionalization approach provided excellent control over the extent of PEI labeling, improved SPION magnetic resonance imaging (MRI) contrast enhancement and produced an efficient transfection agent.