Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination

Tumor hypoxia is known to be one of critical reasons that limit the efficacy of cancer therapies, particularly photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is needed in the process of cancer cell destruction. Herein, taking advantages of the great biocompatibility and high oxygen dissolving ability of perfluorocarbon (PFC), we develop an innovative strategy to modulate the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle for ultrasound triggered tumor-specific delivery of oxygen. In our experiment, nanodroplets of PFC stabilized by albumin are intravenously injected into tumor-bearing mice under hyperoxic breathing. With a low-power clinically adapted ultrasound transducer applied on their tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly release oxygen in the tumor under ultrasound stimulation, and then circulate back into the lung for reoxygenation. Such repeated cycles would result in dramatically enhanced tumor oxygenation and thus remarkably im...

Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies

3.2.1. Linear F-Alkyl/H-Alkyl Diblocks 1720 3.2.2. Unsaturated Diblocks 1721 3.2.3. Branched Diblocks 1722 3.2.4. Diblocks with Heteroatoms 1723 3.2.5. Diblocks with Heavy Halogens 1724 3.3. Triblocks and Multiblocks 1724 3.3.1. FnHmFn Triblocks 1724 3.3.2. HmFnHm Triblocks 1725 3.3.3. Star-Shaped Triblocks 1725 3.3.4. Multiblocks and Polyaffine Compounds 1726 4. Basic Properties of (F-Alkyl)alkyl Diblocks 1726 4.1. The “Polarity” Issues“Apolar”, yet Dipolar 1726 4.2. Surfactant Properties 1727 4.2.1. Surfactant Effects of FnHm Diblocks at Interfaces with Air, Fluorocarbons, and Hydrocarbons 1728

Chemistry, physical chemistry, and uses of molecular fluorocarbon--hydrocarbon diblocks, triblocks, and related compounds--unique "apolar" components for self-assembled colloid and interface engineering.

Ultrasound-Mediated Tumor Imaging and Nanotherapy using Drug Loaded, Block Copolymer Stabilized Perfluorocarbon Nanoemulsions

Background: Synthetic nanoparticles are emerging as versatile tools in biomedical applications, particularly in the area of biomedical imaging. Nanoparticles 1 – 100 nm in diameter have dimensions comparable to biological functional units. Diverse surface chemistries, unique magnetic properties, tunable absorption and emission properties, and recent advances in the synthesis and engineering of various nanoparticles suggest their potential as probes for early detection of diseases such as cancer. Surface functionalization has expanded further the potential of nanoparticles as probes for molecular imaging. Objective: To summarize emerging research of nanoparticles for biomedical imaging with increased selectivity and reduced nonspecific uptake with increased spatial resolution containing stabilizers conjugated with targeting ligands. Methods: This review summarizes recent technological advances in the synthesis of various nanoparticle probes, and surveys methods to improve the targeting of nanoparticles for...

Nanoparticles for biomedical imaging

Perfluorocarbon (PFC) nanoparticles can serve as a platform technology for molecular imaging and targeted drug-delivery applications. These nanoparticles are approximately 250 nm in diameter and are encapsulated in a phospholipid shell, which provides an ideal surface for the incorporation of targeting ligands, imaging agents and drugs. For molecular imaging, PFC nanoparticles can carry very large payloads of gadolinium to detect pathological biomarkers with magnetic resonance imaging. A variety of different epitopes, including alpha(v)beta(3)-integrin, tissue factor and fibrin, have been imaged using nanoparticles formulated with appropriate antibodies or peptidomimentics as targeting ligands. Lipophilic drugs can also be incorporated into the outer lipid shell of nanoparticles for targeted delivery. Upon binding to the target cell, the drug is exchanged from the particle surfactant monolayer to the cell membrane through a novel process called 'contact facilitated drug delivery'. By combining targeted molecular imaging and localized drug delivery, PFC nanoparticles provide diagnosis and therapy with a single agent.

Emerging nanomedicine opportunities with perfluorocarbon nanoparticles

The invention is directed to methods for the delivery of a therapeutic agent using lipid-encapsulated particles containing the therapeutic agent and ultrasound energy. For example, it particularly relates to the use of ultrasound with a lipid-encapsulated emulsion comprising an oil where the emulsion is coupled a targeting ligand and comprises a therapeutic agent.

Enhanced drug delivery

We have designed multifunctional nanoparticulate reporter bioprobes capable of targeting vascular cell adhesion molecule 1 (VCAM1), which is up-regulated in numerous inflammatory processes. These perfluorocarbon-cored nanoparticles emit a unique 19 F magnetic resonance (MR) signature, providing the potential to localize and quantify VCAM-1 expression in early atherosclerosis. NanoparticleVCAM-1 targeting specificity was confirmed by in vitro binding and competition studies. ApoE-null and control C57-BL6 mice (n = 6/ group), fed a Western diet for 35 weeks, were injected i.v. with targeted or non-targeted nanoparticles. After two hours, kidneys were excised and prepared for analysis. ApoE-null kidneys exhibited increased VCAM-1-targeted nanoparticle content over healthy controls by 19 F MR spectroscopy (36.5+8.8 vs. 9.3+2.2 × 10 8 /g, P b .05), which correlated with increased VCAM-1 staining (2.5 ± 1.3% vs. 0.9 ± 0.3%, P b .05); their relative biodistributions were confirmed by fluorescence microscopy and MR imaging. These molecular imaging agents offer new approaches for detection, quantification, and longitudinal evaluation of early inflammation utilising 19 F MR spectroscopy and imaging. From the Clinical Editor: Multifunctional nanoparticulate reporter bioprobes capable of targeting vascular cell adhesion molecule 1 (VCAM-1) are reported in this paper. These perfluorocarbon-cored nanoparticles offer new approaches for detection, quantification, and longitudinal evaluation of early inflammation utilising 19F MR spectroscopy and imaging.

Original Article: Diagnostic Nanomedicine, MRI Renal vascular inflammation induced by Western diet in ApoE-null mice quantified by 19 F NMR of VCAM-1 targeted nanobeacons

Emulsions preferably of nanopartides formed from high boiling liquid perfluorochemical substances, said particles coated with a lipid/surfactant coating are made specific to regions of activated endothelial cells by coupling said nanoparticles to a ligand specific for QvP3 integrin, other than an antibody. The nanoparticles may further include biologically active agents, radionuclides, or other imaging agents.

Integrin targeted imaging agents

Emulsions preferably of nanoparticles formed from oil compounds coupled to a high Z number atom, said particles coated with a lipid/surfactant coating. The nanoparticles are made specific to targeted cells or tissues by coupling said nanoparticles to a ligand specific for the target cells or tissues. The nanoparticles may further include biologically active agents, radionuclides and/or other imaging agents.

Samuel A. Wickline

Papers

Emerging nanomedicine opportunities with perfluorocarbon nanoparticles

Enhanced drug delivery

Original Article: Diagnostic Nanomedicine, MRI Renal vascular inflammation induced by Western diet in ApoE-null mice quantified by 19 F NMR of VCAM-1 targeted nanobeacons

Integrin targeted imaging agents

Emulsion particles for imaging and therapy and methods of use thereof