Showing papers by "C. Shad Thaxton published in 2015"

Nanoparticle Targeting and Cholesterol Flux Through Scavenger Receptor Type B-1 Inhibits Cellular Exosome Uptake.

Abstract: Exosomes are nanoscale vesicles that mediate intercellular communication Cellular exosome uptake mechanisms are not well defined partly due to the lack of specific inhibitors of this complex cellular process Exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts, and can be blocked by non-specific depletion of plasma membrane cholesterol Scavenger receptor type B-1 (SR-B1), found in lipid rafts, is a receptor for cholesterol-rich high-density lipoproteins (HDL) We hypothesized that a synthetic nanoparticle mimic of HDL (HDL NP) that binds SR-B1 and removes cholesterol through this receptor would inhibit cellular exosome uptake In cell models, our data show that HDL NPs bind SR-B1, activate cholesterol efflux, and attenuate the influx of esterified cholesterol As a result, HDL NP treatment results in decreased dynamics and clustering of SR-B1 contained in lipid rafts and potently inhibits cellular exosome uptake Thus, SR-B1 and targeted HDL NPs provide a fundamental advance in studying cholesterol-dependent cellular uptake mechanisms

Synthetic high-density lipoprotein-like nanoparticles as cancer therapy.

Abstract: High-density lipoproteins (HDL) are diverse natural nanoparticles that carry cholesterol and are best known for the role that they play in cardiovascular disease. However, due to their unique targeting capabilities, diverse molecular cargo, and natural functions beyond cholesterol transport, it is becoming increasingly appreciated that HDLs are critical to cancer development and progression. Accordingly, this chapter highlights ongoing research focused on the connections between HDL and cancer in order to design new drugs and targeted drug delivery vehicles. Research is focused on synthesizing biomimetic HDL-like nanoparticles (NP) that can be loaded with diverse therapeutic cargo (e.g., chemotherapies, nucleic acids, proteins) and specifically targeted to cancer cells. Beyond drug delivery, new data is emerging that HDL-like NPs may be therapeutically active in certain tumor types, for example, B cell lymphoma. Overall, HDL-like NPs are becoming increasingly appreciated as targeted, biocompatible, and efficient therapies for cancer, and may soon become indispensable agents in the cancer therapeutic armamentarium.

Mesophase in a thiolate-containing diacyl phospholipid self-assembled monolayer.

Abstract: Maintaining the intrinsic features of mesophases is critically important when employing phospholipid self-assemblies to mimic biomembranes. Inorganic solid surfaces provide platforms to support, guide, and analyze organic self-assemblies but impose upon them a tendency to form well-ordered phases not often found in biomembranes. To address this, we measured mesophase formation in a thiolate self-assembled monolayer (SAM) of diacyl phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphothioethanol (DPPTE) on Au(111), and provide thermodynamic analysis on the mixing behavior of inequivalent DPPTE acyl chains. Our work has uncovered three fundamental issues that enable mesophase formation: (1) Elimination of templating effects of the solid surface, (2) Weakening intermolecular and molecule-substrate interactions in adsorbates, and (3) Equilibrium through entropy-driven self-assembly. Thus, our work provides a more holistic understanding of phase behavior, from liquid phases to mesophases to highly crystalline phases, in organic self-assemblies on solid surfaces, which may extend their applications in nanodevices and to the wider fields of biology and medicine.

High density lipoprotein nanoparticles for inflammation

Abstract: The invention in aspects relates to methods of treating sepsis using HDL-NP The methods include the use of nanoparticles having a core and a lipid based shell with optimal lipids therein

Nanostructures for modulating intercellular communication and uses thereof

Abstract: Nanostructures, compositions and methods for treating vesicle-related or exosome-related conditions are provided. In some cases, the nanostructures and/or compositions may be used to treat cancers, neurological disorders, rheumatologic disorders, viral disorders or other diseases or conditions at least in part by regulating vesicle uptake. Methods of analyzing, imaging and modulating vesicles and cellular vesicles processes are also provided.

Abstract 3671: Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs

Abstract: Exosomes are 30-100 nm diameter lipid vesicles produced by most cells. Exosomes carry diverse cargo, such as RNA and proteins. Cancer cells produce an abundant amount of exosomes, which are released from cells of the primary tumor into the tumor microenvironment and the circulation. Data show that exosomes can promote cancer progression and metastasis by delivering, for instance, pro-metastatic factors to pre-metastatic sites. It is not currently possible to specifically separate tumor-derived exosomes from complex matrices. This ability would provide a better understanding of their contribution to tumorigenesis and cancer progression. Furthermore, the targeting properties of exosomes make them appealing vehicles for encapsulating and delivering therapeutic cargo. However, it is challenging to isolate and then load exosomes with specific drugs. Uniquely, our data reveal that synthetic high-density lipoprotein nanoparticles (HDL NPs) can be tailored to achieve cell-specific exosome labeling and loading of therapeutic cargo. HDL NPs are synthesized using a 5 nm diameter spherical gold nanoparticle. The gold NP serves as a template to control size and shape. Apolipoprotein A-I and phospholipids are conjugated to the gold surface, yielding a synthetic HDL NP similar in size, shape, surface chemistry, and function to some natural HDLs. Our data demonstrate that, upon addition of HDL NPs to cultured CWR 22Rv1 prostate cancer cells, they are packaged into exosomes that are secreted from these cells. Furthermore, HDL NPs made using phospholipids functionalized with either biotin or fluorophore molecules leads to the incorporation of the phospholipids into the exosomes. Thus, the specific cell-derived exosomes are labeled with gold, a molecular fluorophore label, and/or biotin. In each case, the specific exosomes are easy to isolate using methods such as fluorescent isolation or by the robust streptavidin-biotin interaction. Isolated exosomes retain the same size and molecular markers as exosomes from untreated cells. Overall, this unique method may provide control over exosomes for a myriad of diagnostic and therapeutic uses. Citation Format: Nicholas L. Angeloni, Kaylin M. McMahon, C. Shad Thaxton. Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2015-3671