Chia-Hung Lee

To develop a carrier for use in enzyme prodrug therapy, Horseradish peroxidase (HRP) was immobilized onto mesoporous silica nanoparticles (IBN-4: Institute of Bioengineering and Nanotechnology), where the nanoparticle surfaces were functionalized with 3-aminopropyltrimethoxysilane and further conjugated with glutaraldehyde. Consequently, the enzymes could be stabilized in nanochannels through the formation of covalent imine bonds. This strategy was used to protect HRP from immune exclusion, degradation and denaturation under biological conditions. Furthermore, immobilization of HRP in the nanochannels of IBN-4 nanomaterials exhibited good functional stability upon repetitive use and long-term storage (60 days) at 4 °C. The generation of functionalized and HRP-immobilized nanomaterials was further verified using various characterization techniques. The possibility of using HRP-encapsulated IBN-4 materials in prodrug cancer therapy was also demonstrated by evaluating their ability to convert a prodrug (indole-3- acetic acid (IAA)) into cytotoxic radicals, which triggered tumor cell apoptosis in human colon carcinoma (HT-29 cell line) cells. A lactate dehydrogenase (LDH) assay revealed that cells could be exposed to the IBN-4 nanocomposites without damaging their membranes, confirming apoptotic cell death. In summary, we demonstrated the potential of utilizing large porous mesoporous silica nanomaterials (IBN-4) as enzyme carriers for prodrug therapy.

Intracellular hydrogen peroxide levels have the potential to be exploited in cancer therapy.

We designed a study for photodynamic therapy (PDT) using chitosan coated Mg–Al layered double hydroxide (LDH) nanoparticles as the delivery system. A Food and Drug Administration (FDA) approved near-infrared (NIR) fluorescent dye, indocyanine green (ICG) with photoactive properties was intercalated into amine modified LDH interlayers by ion-exchange. The efficient positively charged polymer (chitosan (CS)) coating was achieved by the cross linkage using surface amine groups modified on the LDH nanoparticle surface with glutaraldehyde as a spacer. The unique hybridization of organic-inorganic nanocomposites rendered more effective and successful photodynamic therapy due to the photosensitizer stabilization in the interlayer of LDH, which prevents the leaching and metabolization of the photosensitizer in the physiological conditions. The results indicated that the polymer coating and the number of polymer coats have a significant impact on the photo-toxicity of the nano-composites. The double layer chitosan coated LDH–NH₂–ICG nanoparticles exhibited enhanced photo therapeutic effect compared with uncoated LDH–NH₂–ICG and single layer chitosan-coated LDH–NH₂–ICG due to the enhanced protection to photosensitizers against photo and thermal degradations. This new class of organic-inorganic hybrid nanocomposites can potentially serve as a platform for future non-invasive cancer diagnosis and therapy.

An efficient approach for the antimicrobial agent delivery specifically at acidic pH has been proposed. At the outset, functionalized mesoporous nanoparticles (NPs) were examined to verify the success of synthesis while considering the structural properties by various characterizations. The NPs were immobilized with silver–indole-3 acetic acid hydrazide (IAAH–Ag) complexes via a pH-sensitive hydrazone bond, which functioned as a model drug. When the transitional metal complexes with IBN-4-IAAH–Ag were exposed to acidic pH (near pH 5.0), the silver ions were preferentially released (70%) in a controlled manner up to 12 h by pH-sensitive denial of hydrazone bonds. In contrary, a low drug release (about 25%) was seen in physiological buffer (pH 7.4) demonstrating the pH sensitive release of this drug. Furthermore, the antibacterial efficacy of this unique structured sample was tested against the planktonic cells and biofilms of Gram-positive and Gram-negative bacteria with field emission scanning electron microscope in turn measuring the growth curves, formation of lethal reactive oxygen species, protein leakage, and DNA damage. The synthesized pH-sensitive IAAH–Ag complex was found to have high antimicrobial efficacy against multidrug resistant clinical isolates both in planktonic and biofilm states. Going forward, the synthesized nanoconjugates proved a good in vivo efficacy in treating the bacterial infection of mice. These new metal complex-conjugated NPs through a pH-sensitive hydrazone bond opened up a new avenue for the design and synthesis of the next generation antibacterial agents, which would act as an alternative to antibiotics.

Inorganic nanostructured ensembles containing an anionic clay matrix with layered double hydroxide (LDH) were designed in nanooncology for photosensitizer delivery.

To evaluate the role of charge in the nanoparticle distribution we modified the external surface of layered double hydroxide nanoparticles with various organic groups bearing different charges and further a near-infrared (NIR) fluorescent dye (Cy5.5) is conjugated in the layered structure to assess the biodistribution. The functionalized nanocomposites performed as highly efficient contrast agents since Cy5.5 molecule stabilization inside the layered structure can safeguard them from metabolization in the physiological environments. The cell viability, lactate dehydrogenase and hemolytic assays showed no cytotoxicity with an exceptionally low release of both lactate dehydrogenase and hemoglobin from the treated cells. The in vivo biodistribution results disclosed a high accumulation of positive amino-layered double hydroxides (LDHs) in the lungs. In contrast, there is a rapid clearance of negatively charged carboxylate-LDHs from blood flow by liver uptake. Interestingly neutral LDH-PEG5000 showed enhanced blood circulation time, without high fluorescent accumulation in the major organs. In vitro cellular uptake studies from flow cytometry are relevant to the interactions between the nanoparticle surfaces and various cell types and the data are relevant to effects observed for in vivo biodistribution. To further demonstrate that surface functionalization on LDH nanoparticles can promote targeted drug release, we further immobilized hydroxo-substituted cisplatin (CP) on carboxylate-modified LDHs by coordination bonding. Due to the ideal cleaving property of the carboxylate group the coordinated CP can be efficiently released by the increase of acidic proton and Cl⁻ concentration in the endosomal environment. Functionalized LDHs can be successfully employed as targeted drug delivery systems. When the LDH–CP complex accumulate primarily in the targeted organ, the high positive charge on the framework of LDHs cause susceptibility to rapid endocytosis, which facilitates sustained drug release with minimal systemic toxicity providing the apt treatment in the targeted organ.

The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella. Some of these compounds showed potential bioactivities.

Two norcembranoidal diterpenes, 5-episinuleptolide acetate (1) and scabrolide D (2), were isolated from a Formosan octocoral identified as Sinularia sp. The structures of norcembranoids 1 and 2 were established by spectroscopic methods and by comparison of the spectral data with those of known analogues and 1 was proven to be a new natural product. Norcembranoid 1 was found to exhibit cytotoxicity toward a panel of tumor cells.

A novel 15C compound, pseudoalteromone B (1), possessing a novel carbon skeleton, was obtained from a marine bacterium Pseudoalteromonas sp. CGH2XX. This bacterium was originally isolated from a cultured-type octocoral Lobophytum crassum, that was growing in cultivating tanks equipped with a flow-through sea water system. The structure of 1 was established by spectroscopic methods. Pseudoalteromone B (1) displayed a modestly inhibitory effect on the release of elastase by human neutrophils.