intraductal-delivery-x-ray-visualization-ethanol-based-ablative

Intraductal Delivery and X-ray Visualization of Ethanol-Based Ablative Solution for Prevention and Local Treatment of Breast Cancer in Mouse Models

Breast cancer is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For high-risk women, prophylactic ...

Michigan State University

Missouri University of Science and Technology

Rapid dissolution of Bi Nanocrystals (NCs) in lysosomal conditions results in poor biocompatibility. We report that an in situ surface coating of Bi nanocrystals with Ganex® V216, a cosmetic dispersant, limits its dissolution under physiological conditions. These Bi Ganex (BiG) NCs are readily encapsulated in FDA approved polymer poly(dl-lactic-co-glycolic acid) (PLGA) by an oil-in-water emulsion technique and also undergo facile SiO2 coating. BiG NCs in BiG@PLGA and BiG@SiO2 nanoparticles dissolve slowly under physiological conditions and exhibit excellent biocompatibility, as opposed to uncoated Bi NCs. Finally, these Bi nanoconstructs are shown to be strong CT CAs, even at relatively low Bi concentrations. 

Surface engineering of bismuth nanocrystals to counter dissolution.

Chitin is a carbohydrate polymer with unique pharmacological and immunological properties, however, because of its unwieldy chemistry, the synthesis of discreet sized sub-micron particles has not been well reported. This work describes a facile and flexible method to fabricate biocompatible chitin and dibutyrylchitin sub-micron particles. This technique is based on an oil-in-water emulsification/evaporation method and involves the hydrophobization of chitin by the addition of labile butyryl groups onto chitin, disrupting intermolecular hydrogen bonds and enabling solubility in the organic solvent used as the oil phase during fabrication. The subsequent removal of butyryl groups post-fabrication through alkaline saponification regenerates native chitin while keeping particles morphology intact. Examples of encapsulation of hydrophobic dyes and nanocrystals are demonstrated, specifically using iron oxide nanocrystals and coumarin 6. The prepared particles had diameters between 300-400nm for dibutyrylchitin and 500-600nm for chitin and were highly cytocompatible. Moreover, they were able to encapsulate high amounts of iron oxide nanocrystals and were able to label mammalian cells.

Fabrication of magnetic and fluorescent chitin and dibutyrylchitin sub-micron particles by oil-in-water emulsification.

Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous drugs including gadoxetate disodium (Gd-EOB-DTPA). As master pharmacokinetic regulators, the altered expression of OATPs in diabetes could have a profound and clinically significant influence on drug therapies. Here, we report a method to noninvasively measure OATP activity in T2D mice by quantifying the transport of hepatobiliary-specific gadolinium-based contrast agents (GBCAs) within the liver and kidneys using dynamic contrast-enhanced MRI (DCE-MRI). By comparing GBCA uptake in control and OATP knockout mice, we confirmed liver clearance of the hepatobiliary-specific GBCAs, Gd-EOB-DTPA, and gadobenate dimeglumine, primarily though OATP transporters. Then, we measured a reduction in the hepatic uptake of these hepatobiliary GBCAs in T2D / mice, which mirrored significant reductions in the mRNA and protein expression of OATP1A1 and OATP1B2. As these GBCAs are U.S. Food and Drug Administration-approved agents and DCE-MRI is a standard clinical protocol, studies to determine OATP1B1/1B3 deficiencies in human individuals with diabetes can be easily envisioned.

Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes.

The subventricular zone (SVZ) is a neurogenic niche in the mammalian brain, giving rise to migratory neural progenitor cells (NPC). In rodents, it is well-established that neurogenesis decreases with aging. MRI-based cell tracking has been used to measure various aspects of neurogenesis and NPC migration in rodents, yet it has not yet been validated in the context of age-related decrease in neurogenesis. This validation is critical to using these MRI techniques to study changes in neurogenesis that arise in diseases prevalent in aging populations and their combination with advanced cellular therapeutic approaches aiming to combat neurodegeneration. As such, in this work we used MRI-based cell tracking to measure endogenous neurogenesis and cell migration from the SVZ along the rostral migratory stream to the olfactory bulb, for 12 days duration, in rats aged 9 weeks to 2 years old. To enable the specific detection of NPCs by MRI, we injected micron sized particles of iron oxide (MPIOs) into the lateral ventricle to endogenously label cells within the SVZ, which then appeared as hypo-intensive spots within MR images. In vivo MRI data showed that the rate of NPC migration was significantly different between all ages examined, with decreases in the distance traveled and migration rate as age progressed. The total number of MPIO-labeled cells within the olfactory bulb on day 12, was significantly decreased when compared across ages in ex vivo high-resolution scans. We also demonstrate for the first-time, provocative preliminary data suggesting age-dependent MPIO uptake within the dentate gyrus (DG) as well. Histology to identify doublecortin-positive NPCs, verified the decrease in cell labeling as a function of aging, for both regions. The dramatic reduction of NPC labeling within the SVZ observed with MRI, validates the sensitivity of MRI-based cell tracking to neurogenic potential and demonstrates the importance of understanding the impact of age on the relationship of NPC and disease.

In vivo serial MRI of age-dependent neural progenitor cell migration in the rat brain.

A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.

A multimeric MRI contrast agent based on a closo-borane scaffold bearing modified AAZTA chelates on the periphery.

Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant.

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer.

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO@PLGA NPs and TaO@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO. This work solidifies that TaO-based NPs are versatile contrast agents for CT.

Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

Magnetic particle imaging (MPI), using superparamagnetic nanoparticles as an imaging tracer, is touted as a quantitative biomedical imaging technology, but MPI signal properties have never been characterized for magnetic nanoparticles undergoing biodegradation. We show that MPI signal properties can increase or decrease as iron oxide nanoparticles degrade, depending on the nanoparticle formulation and nanocrystal size, and degradation rate and mechanism. Further, we show that long-term in vitro MPI experiments only roughly approximate long-term in vivo MPI signal properties. Further, we demonstrate for the first time, an environmentally sensitive MPI contrast mechanism opening the door to smart contrast paradigms in MPI.

Complex Relationship Between Iron Oxide Nanoparticle Degradation and Signal Intensity in Magnetic Particle Imaging.

Clinical effectiveness of implantable medical devices would be improved with in situ monitoring to ensure device positioning, determine subsequent damage, measure biodegradation, and follow healing. While standard clinical imaging protocols are appropriate for diagnosing disease and injury, these protocols have not been vetted for imaging devices. This study investigated how radiologists use clinical imaging to detect the location and integrity of implanted devices and whether embedding nanoparticle contrast agents into devices can improve assessment. To mimic the variety of devices available, phantoms from hydrophobic polymer films and hydrophilic gels were constructed, with and without computed tomography (CT)-visible TaO and magnetic resonance imaging (MRI)-visible FeO nanoparticles. Some phantoms were purposely damaged by nick or transection. Phantoms were implanted in vitro into tissue and imaged with clinical CT, MRI, and ultrasound. In a blinded study, radiologists independently evaluated whether phantoms were present, assessed the type, and diagnosed whether phantoms were damaged or intact. Radiologists identified the location of phantoms 80% of the time. However, without incorporated nanoparticles, radiologists correctly assessed damage in only 54% of cases. With an incorporated imaging agent, the percentage jumped to 86%. The imaging technique which was most useful to radiologists varied with the properties of phantoms. With benefits and drawbacks to all three imaging modalities, future implanted devices should be engineered for visibility in the modality which best fits the treated tissue, the implanted device's physical location, and the type of required information. Imaging protocols should also be tailored to best exploit the properties of the imaging agents.

Design Considerations to Facilitate Clinical Radiological Evaluation of Implantable Biomedical Structures.

A multimeric MRI blood pool contrast agent based on the -borane motif is reported. Twelve copies of an amphiphilic DTPA chelate with amine end groups are appended on carbonate-functionalized -borane motif using carbamate linkages. The presence of peripheral phenyl groups on the modified DTPA chelates results in high human serum albumin binding, high relaxivity, and excellent contrast enhancement  and .

Article	Year
Surface engineering of bismuth nanocrystals to counter dissolution. Nanoscale\| PubMed ID: 27356280	2016
Fabrication of magnetic and fluorescent chitin and dibutyrylchitin sub-micron particles by oil-in-water emulsification. Acta biomaterialia\| PubMed ID: 27592817	2016
Dynamic Contrast-Enhanced MRI of OATP Dysfunction in Diabetes. Diabetes\| PubMed ID: 30487262	2019
In vivo serial MRI of age-dependent neural progenitor cell migration in the rat brain. NeuroImage\| PubMed ID: 31152841	2019
A multimeric MRI contrast agent based on a closo-borane scaffold bearing modified AAZTA chelates on the periphery. Chemical communications (Cambridge, England)\| PubMed ID: 31559401	2019
Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer. Breast cancer research : BCR\| PubMed ID: 31779648	2019
Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography. Nanoscale\| PubMed ID: 32211669	2020
Complex Relationship Between Iron Oxide Nanoparticle Degradation and Signal Intensity in Magnetic Particle Imaging. ACS applied nano materials\| PubMed ID: 33163909	2020
Design Considerations to Facilitate Clinical Radiological Evaluation of Implantable Biomedical Structures. ACS biomaterials science & engineering\| PubMed ID: 33449622	2021
Amphiphilic DTPA Multimer Assembled on Icosahedral -Borane Motif as High-Performance MRI Blood Pool Contrast Agent. ACS applied bio materials\| PubMed ID: 35006969	2021

Shatadru Chakravarty

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