Development of a Polymer Ultrasound Contrast Agent Incorporating Nested Carbon Nanodots.

Polymer microbubbles have garnered broad interest as potential theranostic agents. However, the capabilities of polymer MBs can be greatly enhanced, particularly regarding the imaging performance and functional versatility of the platform. This study investigates integrating fluorescent carbon nanodots within polylactic acid (PLA) microbubbles.

Determining Ultrasound Parameters for Bursting Polymer Microbubbles for Future Use in Spinal Cord Injury.

Objective: We believe our poly(lactic acid) (PLA) microbubbles are well suited for therapeutic delivery to spinal cord injury (SCI) using ultrasound-triggered bursting. We investigated the feasibility of clinical ultrasound bursting in situ, the optimal bursting parameters in vitro and the loading and release of a model bio-active DNA.

Methods: Microbubbles were tested using clinical ultrasound in a rat cadaver SCI model.

In Vitro and In Vivo Evaluation of Ultrasound-Triggered Release From Novel Spinal Device.

Objectives: Bacterial infection following spinal fusion is a major clinical concern with up to 20% incidence. An ultrasound-triggered bulk-release system to combat postsurgical bacterial survival was designed and evaluated.

Methods: Polylactic acid (PLA) clips were loaded with vancomycin (VAN) and microbubbles (Sonazoid, GE HealthCare) in vitro.

Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer.

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O and LND providing prolonged oxygenation relative to oxygenated microbubbles alone.

Tumoral oxygenation and biodistribution of Lonidamine oxygen microbubbles following localized ultrasound-triggered delivery.

Prior work has shown that microbubble-assisted delivery of oxygen improves tumor oxygenation and radiosensitivity, albeit over a limited duration. Lonidamine (LND) has been investigated because of its ability to stimulate glycolysis, lactate production, inhibit mitochondrial respiration, and inhibit oxygen consumption rates in tumors but suffers from poor bioavailability. The goal of this work was to characterize LND-loaded oxygen microbubbles and assess their ability to oxygenate a human head and neck squamous cell carcinoma (HNSCC) tumor model, while also assessing LND biodistribution.

Development of a Dual Drug-Loaded, Surfactant-Stabilized Contrast Agent Containing Oxygen.

Co-delivery of cancer therapeutics improves efficacy and encourages synergy, but delivery faces challenges, including multidrug resistance and spatiotemporal distribution of therapeutics. To address these, we added paclitaxel to previously developed acoustically labile, oxygen-core, surfactant-stabilized microbubbles encapsulating lonidamine, with the aim of developing an agent containing both a therapeutic gas and two drugs acting in combination. Upon comparison of unloaded, single-loaded, and dual-loaded microbubbles, size (~1.

Shaping the synthesis of surfactant-stabilized oxygen microbubbles to accommodate encapsulated drug.

We have developed oxygen filled microbubbles, SE61 for localized, ultrasound-triggered oxygen delivery to hypoxic tumors prior to radiation therapy. Microbubbles, created by sonication, have a shell composed of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and sorbitan monostearate. Preliminary studies in mice with breast tumor xenographs showed that increases in oxygen partial pressure levels lasted less than 3 min, which is insufficient for most clinical applications.

Gemcitabine-loaded microbubble system for ultrasound imaging and therapy.

Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell.

LC-MS based stability-indicating method for studying the degradation of lonidamine under physical and chemical stress conditions.

Background And Purpose: Lonidamine is a hexokinase II inhibitor, works as an anticancer molecule, and is extensively explored in clinical trials. Limited information prevails about the stability-indicating methods which could determine the forced degradation of lonidamine under stressed conditions. Hence, we report the use of a rapid, sensitive, reproducible, and highly accurate liquid chromatography and mass spectrometry method to analyze lonidamine degradation.

Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model.

Objectives: Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation.

Methods: Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere.

Preserving the Integrity of Surfactant-Stabilized Microbubble Membranes for Localized Oxygen Delivery.

Ultrasound contrast agents consist of stabilized microbubbles. We are developing a surfactant-stabilized microbubble platform with a shell composed of Span 60 (Sorbitan monostearate) and an emulsifying agent, water-soluble vitamin E (α-tocopheryl poly(ethylene glycol) succinate, abbreviated as TPGS), named SE61. The microbubbles act both as an imaging agent and a vehicle for delivering oxygen to hypoxic areas in tumors.

Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles.

Purpose: Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment that has been shown to result in both chemotherapy and radiation therapy resistance. The purpose of this study was to use localized microbubble delivery to overcome hypoxia prior to therapy.

Materials And Methods: In this study, surfactant-shelled oxygen microbubbles were fabricated and injected intravenously to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound in mice with human breast cancer tumors.

Surfactant-stabilized contrast agent on the nanoscale for diagnostic ultrasound imaging.

Ultrasound contrast agents (CA) are generally micron-sized stabilized gas bubbles, injected IV. However, to penetrate beyond the vasculature and accumulate in targets such as tumors, CA must be an order of magnitude smaller. We describe a method of achieving nanometer-sized, surfactant-stabilized CA by differential centrifugation.

Development and characterization of a nano-scale contrast agent.

Agents injected parenterally must be less than approximately 8 microm diameter in order to traverse the capillaries in the pulmonary bed, but these agents remain in the vasculature until they are eliminated from the body by a variety of mechanisms. Targeting of cells outside the capillaries requires agent diameters of less than approximately 700 nm to enable escape through the larger-than-usual pores that have been noted in the leaky vasculature of a tumor. The objective of this study was to test the feasibility of creating a surfactant-stabilized nano-bubble with favorable acoustic properties, and identify the key parameters that influence size, yield and stability.

Characterization of bile ducts in primary biliary cirrhosis and other liver diseases by immunohistochemical demonstration of Lewis(a) or b antigen.

We investigated Lewis(a) and Lewis(b) expression of bile ducts in 68 specimens from various kinds of liver disease. In addition, the number of IgM and IgG synthesizing plasma cells in the hepatic inflammatory reactions were immunostained and counted. We found a statistically significant decrease in the number of bile ducts in PBC (primary biliary cirrhosis) in comparison with either chronic active or persistent hepatitis (CAH/CPH).

[Interpretation of the estrogen receptor content of breast cancer].

The biochemical analysis of estrogen receptor (ER) content, using the DCC (dextran-coated charcoal) method, was compared with different plotting methods of the estrogen-receptor immunocytochemical assay (ER-ICA) in 80 primary breast cancers including 9 metastases under routine conditions. It was evident, that the determined content of estrogen receptors depends on the technique of measurement, as well as the microscopic organizations of the individual carcinomas and should be interpreted in respect of their content of stroma and if possible of tumour heterogeneity.

Two-dimensional electrophoresis of synovial tissue, synovial fluid and serum in patients with rheumatoid arthritis and related diseases.

Using the technique of two-dimensional (2D) electrophoresis with consecutive silver staining, we investigated samples of serum, synovial fluid and synovial tissue obtained from 19 patients suffering from rheumatoid arthritis (RA) or non-RA arthritis. From these experiments we have drawn the following conclusions. 2D electrophoresis of serum, synovial fluid and synovial tissue extracts taken from patients suffering from joint diseases is a reproducible method.

Immunocytochemical detection of sulphonylated DNA in tissue sections. An alternative to Feulgen staining of DNA.

We report here on a new sensitive and highly specific DNA staining technique which we have called sulpho-DNA staining. DNA staining is based on a sulphonylation reaction of 2'-deoxycytidine or cytidine that takes place in the 6th position of cytosine with ensuing immunodetection of the sulphonylated DNA. The specificity of DNA staining is introduced by the use of an antibody recognizing only modified DNA but not modified RNA, by recourse to an additional acid hydrolysis step which destroys RNA but not DNA.