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Abstract A novel EGFR-targeting, thermal-sensitive multifunctional liposome (TSML) was developed based on manganese-doped magnetism-engineered iron oxide nanoparticles (MnMEIOs) and gold nanorods (AuNRs) for efficient photothermal therapy and magnetic resonance (MR) imaging. An Erbitux-conjugated TSML (Erb-TSML) was encapsulated with doxorubicin and gold nanorods conjugated with manganese-doped magnetism-engineered iron oxide nanoparticles, for theranostic applications of EGFR-positive tumors. The Erb-TSML selectively targeted EGFR-positive tumors and promoted tumor destruction by laser activation. Using confocal microscopy, MR and optical imaging, we demonstrated that Erb-TSML specifically bound to A431 tumor cells. No signs of major morphological damages to the normal tissues were observed in mice treated with Erb-TSML and laser, indicating this theranostic platform protected heart against doxorubicin-induced toxicity to normal tissues. These results indicate that the Erb-TSML may be a promising diagnostic and therapeutic platform for EGFR-overexpressing tumors. Graphical Abstract We developed Erbitux conjugated thermal-sensitive multifunctional liposome composed of manganese-doped magnetism-engineered iron oxide nanoparticles, gold nanorods and doxorubicin for targeted delivery to EGFR-positive tumors. The encapsulated gold nanorods and doxorubicin with Erbitux conjugation could specifically target the EGFR-overexpressing tumors and mediate photothermal destruction of tumors by laser activation. Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract: A novel dual functional theranosis platform is developed based on manganese magnetism-engineered iron oxide (MnMEIO) and gold nanorods (AuNRs) to combine magnetic resonance (MR) imaging and photothermal therapy in one nanocluster. The platform showed improved T 2 -weighted MR imaging and exhibited a near-infrared (NIR) induced temperature elevation due to the unique characteristics of AuNRs@MnMEIOs nanoclusters. The obtained dual functional spherical-shaped nanoclusters showed low cytotoxicity, and high cellular uptake efficiency. The AuNRs@MnMEIOs nanoclusters also demonstrated a 1.9 and 2.2 folds r 2 relaxivity value higher than those of monodispersed MnMEIO and Resovist. In addition, in vivo MR imaging study found that the contrast enhancements were – 70.4 ± 4.3% versus – 7.5 ± 3.0% in Her-2/neu overexpression tumors as compared to the control tumors. More importantly, NIR laser irradiation to the tumor site resulted in outstanding photothermal therapeutic efficacy and without damage to the surrounding tissue. In additional, the prepared dual functional AuNRs@MnMEIOs display high stability and furthermore disperse even in the presence of external magnet, showing that AuNRs@MnMEIOs nanoclusters can be manipulated by an external magnetic field. Therefore, such nanoclusters combined MR imaging and photothermal therapeutic functionality can be developed as a promising nanosystem for effective cancer diagnosis and therapy. [Copyright &y& Elsevier]

Recent studies suggest that intratumoral legumain promotes tumorigenesis. To monitor legumain activity in tumors, we developed a new MRI contrast agent ([Gd-NBCB-TTDA-Leg(L)]) and a NIR fluorescence probe (CyTE777-Leg(L)-CyTE807). The MRI contrast agent was prepared by introduction of cyclobutyl and benzyl group residues to TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triaza-dodecanedioic acid), followed by the attachment of a legumain-specific substrate peptide (Leg(L)). The NIR fluorescence probe was designed by conjugating two NIR fluorochromes (CyTE777 and CyTE807) with Leg(L). Peptide cleavage of the MRI contrast agent by legumain can increase its hydrophobicity and promote rotational correlation time (τ R). Peptide cleavage of the NIR probes by the legumain relieves the self quench of the probe. Peptide cleavage of the MRI contrast agent and the NIR fluorescence probe by legumain were confirmed by T 1 relaxometric studies and by fluorescence studies, respectively. In vivo MR images showed that [Gd-NBCB-TTDA-Leg(L)] attained 55.3 fold (254.2% versus 4.6%, at 2.0 h post-injection) higher imaging enhancement, as compared with control contrast agent bearing a noncleaveable peptide ([Gd-NBCB-TTDA-Leg(D)], in the CT-26 (legumain+) tumors. Similarly, optical imaging probe CyTE777-Leg(L)-CyTE807 attained 15.2 fold (3.34 × 109 photons/min versus 0.22 × 109 photons/min, at 24.0 h post-injection) higher imaging enhancement in the CT-26 (legumain+) tumors, compared to a NIR control probe (CyTE777-Leg(D)-CyTE807). These data indicate that the [Gd-NBCB-TTDA-Leg(L)] and the CyTE777-Leg(L)-CyTE807 probes may be promising tools to image the legumain-expressing cancers for diagnoses and targeted treatments. [ABSTRACT FROM AUTHOR]

Abstract: The coupling of specific antibodies to imaging agents often improves imaging specificity. However, free amine groups designed for the coupling can cause nonspecific binding of the imaging agents. We report here development of a nanocarrier, MnMEIO-silane-NH2-mPEG nanoparticles (NPs), consisting of a manganese-doped iron oxide nanoparticle core (MnMEIO), a copolymer shell of silane and amine-functionalized poly(ethylene glycol) (silane-EA-mPEG). The key feature in MnMEIO-silane-NH2-mPEG is the flexible PEG, which masks the non-conjugated reactive amine groups (–NH2 ↔ –NH3 +) and reduces nonspecific binding of MnMEIO-silane-NH2-mPEG to cells. The amine groups on MnMEIO-silane-NH2-mPEG were conjugated with the fluorescent dye, Cy777 or antibodies [Erbitux (Erb)] to form a MR-optical imaging contrast agent (MnMEIO-silane-NH2-(Erb)-mPEG) for EGFR-expressing tumors. Confocal microscopic and flow cytometric analyses showed that MnMEIO-silane-NH2-(Erb)-mPEG displayed low nonspecific binding. Moreover, TEM images showed that MnMEIO-silane-NH2-(Erb)-mPEG were endocytosed by EGFR-expressing cells. In line with their EGFR expression levels, A431, PC-3, and Colo-205 tumors treated with MnMEIO-silane-NH2-(Erb)-mPEG NPs showed −97.1%, −49.7%, and −2.8% contrast enhancement, respectively, in in vitro T 2-weighted MR imaging. In vivo T 2-weighted MR imaging and optical images showed that MnMEIO-silane-NH2-(Erb)-mPEG could specifically and effectively target to EGFR-expressing tumors in nude mice; the relative contrast enhancements were 7.94 (at 2 h) and 7.59 (at 24 h) fold higher in A431 tumors as compared to the EGFR-negative Colo-205 tumors. On the contrary, MnMEIO-silane-NH2-(Erb) NPs showed only 1.44 (at 2 h) and 1.52 (at 24 h) fold higher in EGFR-positive tumors as compared to the EGFR-negative tumors. Finally, antibodies can be readily changed to allow imaging of other tumors bearing different antigens. These data indicate that masking surface charges on contrast agents is a useful strategy to improve imaging efficacy. [Copyright &y& Elsevier]

Abstract: This paper reports the first successful preparation of biotechnological grade agarose from Gelidium amansii found in Taiwan. The scale-efficiency preparation was achieved by shortening EDTA treatment time through dispersing G. amansii agar in water in the presence of heat and EDTA, removing agaropectin impurity with a heat-compatible and strong-anion exchange resin, and precipitating agarose with a cost-effective isopropanol method. The yield of agarose from prepared G. amansii agar was 11.3%. The acquired agarose has a gel strength of 853gcm−2, a sulfate content of 0.14%, a pyruvate content of 1.03%, a degree of electroendosmosis of 0.16 and very limited binding affinity to DNA. The excellent properties of agarose from G. amansii of Taiwan confirm its potential diverse biotechnological applications. This innovative agarose preparation method with the significantly improved scale-efficiency can be modified for large-scale preparation of agarose for use in biotechnological industry and biochemical research. [Copyright &y& Elsevier]

Abstract: Magnetic resonance imaging (MRI) has become the leading imaging tool for providing fine anatomical and physiology details. Optical imaging is offering a sensitive and specific method for in vivo molecular imaging of targeting molecules. The goal of this study is to design, synthesize, and characterize a new target-specific dual contrast agent for MR and optical imaging. Hence, [Gd(TTDA-NP)(H2O)]2− was prepared and characterized. In addition, an 8-amino acid Bombesin analogue (BN) peptide substrate, which can target prostate, breast, and colon cancer, was synthesized by solid-phase peptide synthesis and subsequently conjugated with [Gd(TTDA-NP)(H2O)]2− to form BN conjugated Gd-TTDA-NP-BN. The water-exchange rate for [Gd(TTDA-NP)(H2O)]2− (110×106 s−1) is significantly higher than that of [Gd(DTPA)(H2O)]2− complex and the rotational correlation time (τ R) for [Gd(TTDA-NP)(H2O)]2− (145ps) is also higher than those of [Gd(TTDA)(H2O)]2− (104ps) and [Gd(DTPA)(H2O)]2− (103ps). The Gd-TTDA-NP-BN shows remarkable high relaxivity (7.12mM−1 s−1) comparing to that of [Gd(TTDA-NP)(H2O)]2-. The fluorescence studies showed that the Gd-TTDA-NP-BN could efficiently enter PC-3 cells. Additionally, the human cancer cells xenografts using Gd-TTDA-NP-BN-Cy5.5 as an optical imaging probe clearly visualized subcutaneous PC-3 tumor and demonstrated its targeting ability to the gastrin releasing peptide (GRP) receptor overexpression. Furthermore, the biodistribution studies demonstrated significantly high tumor uptake (25.97±1.07% ID/g) and high tumor-to-normal tissue ratios at one hour post-injection of Gd-TTDA-NP-BN-Cy5.5 in the animal model. These results suggest that the Gd-TTDA-NP-BN-Cy5.5 is a superior probe for in vivo optical imaging. Importantly, the MR imaging studies showed notable signal enhancement (44.9±4.2%) on the tumor, indicating a high level accumulation of the contrast agent within the PC-3 tumor sites. Hence, targeting of prostate cancer cells was observed under in vitro and in vivo MR imaging studies using Gd-TTDA-NP-BN contrast agent. We conclude that Gd-TTDA-NP-BN and Gd-TTDA-NP-BN-Cy5.5 can be potentially used as the contrast agents for targeting GRP receptor overexpressing cells and tumors. [Copyright &y& Elsevier]