DTPAA-Gd Functionalized Ultrasmall Au15NCs Nanohybrids for Multimodal Imaging.

INTRODUCTION: Multimodal imaging agent has the potential to overcome the shortage and incorporate the advantages of different imaging tools for extremely sensitive diagnosis. To achieve multimodal imaging, combining multiple contrast agents into a special nanostructure has become a main strategy; However, the combination of all of these functions into one nanoplatform usually requires a complicated synthetic procedure that results in heterogeneous nanostructure. METHODS: In this study, we develop ultrasmall gold nanoclusters with 15 gold atoms (Au15NCs) functionalized with diethylenetriamine-pentaacetic acid dianhydride (DTPAA-Gd) as an optimized multimodal imaging agent to enhance imaging ability. RESULTS: The Au15NCs-DTPAA-Gd nanohybrids possess the ultra-small size and are capable of enhancing the contrast in near-infrared fluorescence (NIRF), magnetic resonance (MR) and X-ray computed tomography (CT) imaging. Meanwhile, the integrated DTPAA-Gd component not only endow the nanohybrids to produce higher T1 relaxivity (r1 = 21.4 mM-1 s-1) than Omnipaque (r1 = 3.973 mM-1s-1) but also further enhance X-ray attenuation property of Au15NCs. Importantly, the fluorescence intensity of Au15NCs-DTPAA-Gd did not decrease compared with Au15NCs. Ultimately, in vivo imaging experiments have demonstrated that Au15NCs-DTPAA-Gd nanohybrids can be quickly eliminated from the body through the urinary system and has great potential for anatomical imaging. CONCLUSION: These data manifest Au15NCs-DTPAA-Gd present great potential as a multimodal contrast agent for disease diagnosis, especially for early accurate detection of tumors.

Pulmonary biodistribution and cellular uptake of intranasally administered monodisperse particles.

PURPOSE: For the rational design of nanovaccines against respiratory pathogens, careful selection of optimal particle size and chemistry is paramount. This work investigates the impact of these properties on the deposition, biodistribution, and cellular interactions of nanoparticles within the lungs. METHOD: In this work, biodegradable poly(sebacic anhydride) (poly(SA)) nanoparticles of multiple sizes were synthesized with narrow particle size distributions. The lung deposition and retention as well as the internalization by phagocytic cells of these particles were compared to that of non-degradable monodisperse polystyrene nanoparticles of similar sizes. RESULTS: The initial deposition of intranasally administered particles in the lungs was dependent on primary particle size, with maximal deposition occurring for the 360-470 nm particles, regardless of chemistry. Over time, both particle size and chemistry affected the frequency of particle-positive cells and the specific cell types taking up particles. The biodegradable poly(SA) particles associated more closely with phagocytic cells and the dynamics of this association impacted the clearance of these particles from the lung. CONCLUSIONS: The findings reported herein indicate that both size and chemistry control the fate of intranasally administered particles and that the dynamics of particle association with phagocytic cells in the lungs provide important insights for the rational design of pulmonary vaccine delivery vehicles.

Poly(sebacic anhydride) nanocapsules as carriers: effects of preparation parameters on properties and release of doxorubicin.

Poly(sebacic anhydride) (PSA) is a promising polymer for the production of drug delivery vehicles. The aim of this work is to study the effect of preparation parameters on the quality of the nanoparticles. In this study, doxorubicin (DOX)-loaded PSA nanocapsules were prepared by an emulsion method. Effects of factors such as type of organic solvent, co-solute (surfactant) and its concentration on drug-loading efficiency, particle size and size distribution, morphology and release profile were examined to gain insight in the preparation and stability of nanostructures. Particles with sizes in the range of 218-1198 nm were prepared. The smallest particles with a narrow size distribution were prepared by using polyvinyl alcohol as a co-solute and dichloromethane as a solvent. Efficiency and intracellular release of doxorubicin from the formulated particles were studied on MDA-MB-231 cells. It was observed that DOX-loaded PSA particles can diffuse into the cells and intracellular antitumour activity is directly related to the released amount of drug from the PSA nanocapsules.

Synthesis, characterization, and cellular uptake of magnetic nanocarriers for cancer drug delivery.

HYPOTHESIS: The absence of targetability is the primary inadequacy of conventional chemotherapy. Targeted drug delivery systems are conceptualized to overcome this challenge. We have designed a targetable magnetic nanocarrier consisting of a superparamagnetic iron oxide (SPIO) core and biocompatible and biodegradable poly(sebacic anhydride)-block-methyl ether poly(ethylene glycol) (PSA-mPEG) polymer shell. The idea is that this type of carriers should facilitate the targeting of cancer cells. EXPERIMENTS: PSA-mPEG was synthesized with poly-condensation and the in vitro degradation rate of the polymer was monitored by gel permeation chromatography (GPC). The magnetic nanocarriers were fabricated devoid of any surfactants and were capable of carrying high payload of hydrophobic dye. The successful encapsulation of SPIO within the polymer shell was confirmed by TEM. The results we obtained from measuring the size of SPIO loaded in polymeric NPs (SPIO-PNP) by dynamic light scattering (DLS) and iron content measurement of these particles by ICP-MS, indicate that SPIO is the most suitable carrier for cancer drug delivery applications. FINDINGS: Measuring the hydrodynamic radii of SPIO-PNPs by DLS over one month revealed the high stability of these particles at both body and room temperature. We further investigated the cell viability and cellular uptake of SPIO-PNPs in vitro with MDA-MB-231 breast cancer cells. We found that SPIO-PNPs induce negligible toxicity within a concentration range of 1-2µg/ml. The TEM micrographs of thin cross-sectioned MDA-MBA-231 cells showed internalization of SPIO-PNPs within size range of 150-200nm after 24h. This study has provided a foundation for eventually loading these nanoparticles with anti-cancer drugs for targeted cancer therapy using an external magnetic field.

Toxicity studies of poly(anhydride) nanoparticles as carriers for oral drug delivery.

PURPOSE: To evaluate the acute and subacute toxicity of poly(anhydride) nanoparticles as carriers for oral drug/antigen delivery. METHODS: Three types of poly(anhydride) nanoparticles were assayed: conventional (NP), nanoparticles containing 2-hydroxypropyl-ß-cyclodextrin (NP-HPCD) and nanoparticles coated with poly(ethylene glycol) 6000 (PEG-NP). Nanoparticles were prepared by a desolvation method and characterized in terms of size, zeta potential and morphology. For in vivo oral studies, acute and sub-acute toxicity studies were performed in rats in accordance to the OECD 425 and 407 guidelines respectively. Finally, biodistribution studies were carried out after radiolabelling nanoparticles with (99m)technetium. RESULTS: Nanoparticle formulations displayed a homogeneous size of about 180 nm and a negative zeta potential. The LD(50) for all the nanoparticles tested was established to be higher than 2000 mg/kg bw. In the sub-chronic oral toxicity studies at two different doses (30 and 300 mg/kg bw), no evident signs of toxicity were found. Lastly, biodistribution studies demonstrated that these carriers remained in the gut with no evidences of particle translocation or distribution to other organs. CONCLUSIONS: Poly(anhydride) nanoparticles (either conventional or modified with HPCD or PEG6000) showed no toxic effects, indicating that these carriers might be a safe strategy for oral delivery of therapeutics.

2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride. A novel and highly potent anti-inflammatory and cytoprotective agent.

2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (CDDO anhydride) has been synthesized, which is the first example of an oleanane triterpenoid anhydride. CDDO anhydride shows potency similar to or higher than the corresponding acid (CDDO) in various in vitro and in vivo assays related to inflammation and carcinogenesis. Notably, preliminary phamacokinetics studies show that CDDO anhydride levels are higher than CDDO levels in mouse tissues and blood. Further evaluation of CDDO anhydride is in progress.

Chirality in supramolecular self-assembled monolayers of achiral molecules on graphite: formation of enantiomorphous domains from arachidic anhydride.

The molecular arrangement and chirality of the self-assembled arachidic anhydride monolayer on graphite were investigated using scanning tunneling microscopy (STM). This molecule has two identical alkyl chains, linked by an anhydride group in the middle. In its extended form, one alkyl chain is shifted, with respect to the other, along the molecular backbone. Upon adsorption on graphite, this achiral anhydride spontaneously forms two types of homogeneous domains (denoted as m and m') with mirror symmetry. The angle from the molecular chain to the row-packing direction is 98.0 degrees +/- 0.5 degrees and 82.0 degrees +/- 0.5 degrees for domains m and m', respectively. Domain m is the mirror image of m'. The molecular arrangement of this self-assembled monolayer shows that domains m and m' are two-dimensional enantiomers with opposite chiralities. This new molecular packing motif is confirmed by line-profile analyses along the molecule-chain and the row-packing directions. This finding demonstrates the spontaneous formation of highly ordered homogeneous enantiomorphous domains on graphite resulting only from weak van der Waals forces between the achiral arachidic anhydride molecules.

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.

Anhydride prodrugs for nonsteroidal anti-inflammatory drugs.

PURPOSE: The objective of this study was to synthesize anhydride prodrugs for prolong action to shield the carboxylic acid group from irritative effects and to temporary hydrophobize the drug so that it becomes accessible to aqueous media when the anhydride residue is hydrolyzed. METHODS: Ibuprofen, a nonsteroidal anti-inflammatory agent, was used as a representative drug for anhydride derivatization. Mixed anhydrides of ibuprofen with fatty acids of different chain length were prepared by reacting acid chloride derivatives with the corresponding acid in the presence of acid acceptor and two-phase reaction. Mixed anhydrides were also prepared by dehydration reaction using acetic anhydride and anhydride interchange of symmetric anhydrides. The analgesic effects of mixed anhydride prodrugs were tested using nonsteroidal anti-inflammatory drug rat paw edema model. In vitro degradation of mixed anhydrides and drug release were monitored by high-performance liquid chromatography. RESULTS: Ibuprofen was bound to aliphatic and aromatic acids via an anhydride bond in high reaction yields (>85%) with high mixed anhydride content (>80%). The mix anhydride was purified by chromatography and stored at 4 degrees C to minimize conversion into the symmetric anhydride. These anhydride derivatives hydrolyzed at different time intervals depending on the hydrophobicity of conjugated acid. In vivo testing of the ibuprofen anhydride derivatives for analgesic effect indicated an extended action of the drug for over 24 h as a function of the fatty acid chain length. CONCLUSION: This study demonstrates the promise of anhydride prodrugs for extending drug action and shielding the carboxylic acid group.