Superparamagnetic iron oxide nanoparticles (SPION) are extensively used for magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), as well as for magnetic fluid hyperthermia (MFH). We here describe a sequential centrifugation protocol to obtain SPION with well-defined sizes from a polydisperse SPION starting formulation, synthesized using the routinely employed co-precipitation technique. Transmission electron microscopy, dynamic light scattering and nanoparticle tracking analyses show that the SPION fractions obtained upon size-isolation are well-defined and almost monodisperse. MRI, MPI and MFH analyses demonstrate improved imaging and hyperthermia performance for size-isolated SPION as compared to the polydisperse starting mixture, as well as to commercial and clinically used iron oxide nanoparticle formulations, such as Resovist ® and Sinerem ®. The size-isolation protocol presented here may help to identify SPION with optimal properties for diagnostic, therapeutic and theranostic applications.
a b s t r a c tColorless, non-fluorescent Chl-catabolites (NCCs) are the typical, ubiquitous products of chlorophyll (Chl)-breakdown in senescent leaves. However, a fluorescent Chl-catabolite (FCC) accumulated in de-greened leaves of Spathiphyllum wallisii (Peace Lily), which showed a weak blue luminescence. The FCC, named Sw-FCC-62, was 'hypermodified' with an unprecedented 6-(2-[3,4-dihydroxy-phenyl]-ethyl)-b-glucopyranosidyl ester at the propionyl group. Such esters stabilize FCCs against their typical and rapid, spontaneous isomerization to NCCs. Chl-breakdown in Sp. wallisii thus branches off from the 'common' path in leaves, and furnishes unique and 'persistent' FCCs. Our findings on 'hypermodified' FCCs also call for attention as to possible physiological roles of Chl-catabolites in plants.
Yellow leaves of bananas glow blue under UV light. The luminescence is caused by uniquely glycosylated (“hypermodified”) chlorophyll catabolites that accumulate in senescent banana leaves. These findings suggest that (some) chlorophyll catabolites are not mere detoxification products, but are likely to play still unknown physiological roles.
Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are not only able to accumulate via the EPR effect but also to extravasate, target specific cell populations, and get internalized by cells. Reasoning that antibodies are among the most efficient targeting systems developed by nature, we consider their size (∼10-15 nm) to be ideal for balancing passive and active tumor targeting. Therefore, small, short-circulating (10 kDa, ∼7 nm, t ∼ 1 h) and larger, longer-circulating (40 kDa, ∼13 nm, t ∼ 13 h) riboflavin-targeted branched PEG polymers were synthesized, and their biodistribution and target site accumulation were evaluated in mice bearing angiogenic squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3) xenografts. The tumor accumulation of the 10 kDa PEG was characterized by rapid intercompartmental exchange and significantly improved upon active targeting with riboflavin (RF). The 40 kDa PEG accumulated in tumors four times more efficiently than the small polymer, but its accumulation did not profit from active RF-targeting. However, RF-targeting enhanced the cellular internalization in both tumor models and for both polymer sizes. Interestingly, the nanocarriers' cell-uptake in tumors was not directly correlated with the extent of accumulation. For example, in both tumor models the small RF-PEG accumulated much less strongly than the large passively targeted PEG but showed significantly higher intracellular amounts 24 h after iv administration. Additionally, the size of the polymer determined its preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest uptake of the 40 kDa RF-PEGs was observed in tumor-associated macrophages. These findings imply that drug carriers with sizes in the range of therapeutic antibodies show balanced properties with respect to passive accumulation, tissue penetration, and active targeting. Besides highlighting the potential of RF-mediated (cancer) cell targeting, we show that strong tumor accumulation does not automatically mean high cellular uptake and that the nanocarriers' size plays a critical role in cell- and compartment-specific drug targeting.
Chlorophyll breakdown is a visual phenomenon of leaf senescence and fruit ripening. It leads to the formation of colorless chlorophyll catabolites, a group of (chlorophyll-derived bilin-type) linear tetrapyrroles. Here, analysis and structure elucidation of the chlorophyll breakdown products in leaves of banana (Musa acuminata) is reported. In senescent leaves of this monocot all chlorophyll catabolites identified were hypermodified fluorescent chlorophyll catabolites (hmFCCs). Surprisingly, nonfluorescent chlorophyll catabolites (NCCs) were not found, the often abundant and apparently typical final chlorophyll breakdown products in senescent leaves. As a rule, FCCs exist only fleetingly, and they isomerize rapidly to NCCs in the senescent plant cell. Amazingly, in the leaves of banana plants, persistent hmFCCs were identified that accounted for about 80 % of the chlorophyll broken down, and yellow leaves of M. acuminata display a strong blue luminescence. The structures of eight hmFCCs from banana leaves were analyzed by spectroscopic means. The massive accumulation of the hmFCCs in banana leaves, and their functional group characteristics, indicate a chlorophyll breakdown path, the downstream transformations of which are entirely reprogrammed towards the generation of persistent and blue fluorescent FCCs. As expressed earlier in related studies, the present findings call for attention, as to still elusive biological roles of these linear tetrapyrroles.
Photoacoustic imaging (PAI) is increasingly employed in (pre‐) clinical research, thus, development of suitable contrast agents, in particular fluorescence‐quenched chromophores, for PAI is of high importance. Small molecule dyes are appropriate due to favorable circulation, excretion properties, and ease of conjugation to targeting moieties. The BODIPY chromophores have been widely used in bioimaging, yet they are not ideal for PAI due to high fluorescence. Hence, here nonfluorescent BODIPY are designed by 1H‐pyrrole conjugation (PyBODIPY) to apply as probes for PAI. The PyBODIPYs exhibit absorption maxima up to 800 nm, and PA signal could be detected in concentrations of 1 nmol mL−1 and 35 pmol mm−3, by tube and tissue phantom, respectively. In addition to nonfluorescent, PyBODIPYs are non‐phototoxic, photostable, and show high molar extinction coefficients, as well as inertness toward nucleophilic addition. PyBODIPYs are modified with PEG‐400, to improve aqueous solubility and to enable in vivo imaging. Thus, PyBODIPY is an attractive small molecule to use as PA contrast agent, which could be coupled to targeting ligands for in vivo use. In addition, 1H‐pyrrole conjugation might be applied to the design of novel near‐infrared ranged quenchers suitable for PAI, and promote the development of probes for clinical translation.
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