Pharmacokinetics and toxicodynamics of intravenously administered rigid microparticles that passively target the pulmonary circulation of rodents

Systemic treatment of localized diseases, currently the most widely used method of drug delivery, often results in dose limiting toxicity. Reducing the amount of drug administered to minimize toxicity often reduces treatment effectiveness. Many drug delivery systems actively target their site based on an over-expression of cell surface receptors that may differ during disease or treatment progression. The purpose of this thesis was to determine the optimal size/number of intravenously administered rigid polystyrene microparticles (MPs) that are passively filtered by the pulmonary circulation system prior to causing dose-limiting toxicity and to develop an appropriately sized rigid yet biodegradable MP for future use. Passive entrapment of MPs in the lung depended upon size. In a rat model, rigid, non-degradable 10 μm polystyrene MPs were trapped in the lung capillary and remained for the duration of the 1-week study. Smaller MPs (6 μm) were initially trapped in the lung but migrated to the liver and spleen over 48 h whereas 3 μm MPs eluded the lung’s filtering capability and became entrapped in the liver by 1 h. To devise a non-invasive technique to detect early toxicity, a mathematical algorithm based on a clinically-relevant, non-invasive method developed in humans was adapted to study pulmonary gas exchange in young CD-1 mice. A threshold MP dosage that resulted in a rapid decrease in function was found for different MP sizes. The ventilation-perfusion ratio (VA/Q) was dramatically reduced from pre-treatment to Day 1 post-treatment when ≥550,000 10 μm MPs/g, ≥40,000 25 μm MPs/g or ≥4,000 45 μm MPs/g were administered. Shunt increased slightly with MP burden but was not a consistent early marker for impaired gas exchange from microemboli. Of interest was that by Day 7, the resulting hypoxemia was resolved. Finally, the manufacture of biodegradable, albumin-based MPs was optimized to create an appropriately-sized narrow distribution using an emulsion technique. Increased heating (150 °C vs. 120 °C) caused an increase in lysinoalanine formation and decreased the lung clearance rate, while not changing MP size. In summary, understanding of the pharmacokinetics, toxicodynamics, and design of passively targeted intravenously administered MPs was significantly advanced.Ph. D.Includes bibliographical referencesIncludes vitaby Hilliard L. Kutsche

Photoacoustic and Magnetic Resonance Imaging of Hybrid Manganese Dioxide-Coated Ultra-Small NaGdF4 Nanoparticles for Spatiotemporal Modulation of Hypoxia in Head and Neck Cancer

There is widespread interest in developing agents to modify tumor hypoxia in head and neck squamous cell carcinomas (HNSCC). Here, we report on the synthesis, characterization, and potential utility of ultra-small NaYF4:Nd3+/NaGdF4 nanocrystals coated with manganese dioxide (usNP-MnO2) for spatiotemporal modulation of hypoxia in HNSCC. Using a dual modality imaging approach, we first visualized the release of Mn2+ using T1-weighted magnetic resonance imaging (MRI) and modulation of oxygen saturation (%sO2) using photoacoustic imaging (PAI) in vascular channel phantoms. Combined MRI and PAI performed in patient-derived HNSCC xenografts following local and systemic delivery of the hybrid nanoparticles enabled mapping of intratumoral nanoparticle accumulation (based on T1 contrast enhancement) and improvement in tumor oxygenation (increased %sO2) within the tumor microenvironment. Our results demonstrate the potential of hybrid nanoparticles for the modulation of tumor hypoxia in head and neck cancer. Our findings also highlight the potential of combined MRI-PAI for simultaneous mapping nanoparticle delivery and oxygenation changes in tumors. Such imaging methods could be valuable in the precise selection of patients that are likely to benefit from hypoxia-modifying nanotherapies

Dual Regioselective Targeting the Same Receptor in Nanoparticle-Mediated Combination Immuno/Chemotherapy for Enhanced Image-Guided Cancer Treatment

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Tunable Narrow Band Emissions from Dye-Sensitized Core/Shell/Shell Nanocrystals in the Second Near-Infrared Biological Window

We introduce a hybrid organic–inorganic system consisting of epitaxial NaYF₄:Yb³⁺/X³⁺@NaYbF₄@NaYF₄:Nd³⁺ (X = null, Er, Ho, Tm, or Pr) core/shell/shell (CSS) nanocrystal with organic dye, indocyanine green (ICG) on the nanocrystal surface. This system is able to produce a set of narrow band emissions with a large Stokes-shift (>200 nm) in the second biological window of optical transparency (NIR-II, 1000–1700 nm), by directional energy transfer from light-harvesting surface ICG, via lanthanide ions in the shells, to the emitter X³⁺ in the core. Surface ICG not only increases the NIR-II emission intensity of inorganic CSS nanocrystals by ∼4-fold but also provides a broadly excitable spectral range (700–860 nm) that facilitates their use in bioapplications. We show that the NIR-II emission from ICG-sensitized Er³⁺-doped CSS nanocrystals allows clear observation of a sharp image through 9 mm thick chicken breast tissue, and emission signal detection through 22 mm thick tissue yielding a better imaging profile than from typically used Yb/Tm-codoped upconverting nanocrystals imaged in the NIR-I region (700–950 nm). Our result on in vivo imaging suggests that these ICG-sensitized CSS nanocrystals are suitable for deep optical imaging in the NIR-II region