Dongsik Park

A platform for nitric oxide delivery

Nitric oxide (NO) is one of the structurally smallest pharmaceutical molecules, which shows great potential as an anti-restenosis, wound healing, anticancer, and antibacterial agent. To date, while most of the studies have focused mainly on demonstrating the versatility of the NO-releasing materials, little effort has been made on developing successful NO-delivery strategies for advancing NO-mediated therapy. Thus, the quest for a rationally designed NO-delivery system is becoming one of the important issues in the biomedical applications of NO. This feature article discusses the overall research trends in the NO-delivery, focusing mainly on the various particle-type and coating platforms. The objective of this article is not only to highlight the fundamental principle and challenges associated with NO-delivery, but also to provide insight for the further development of novel NO-delivery platforms for clinical applications in the near future.

Phenylboronic acid-sugar grafted polymer architecture as a dual stimuli-responsive gene carrier for targeted anti-angiogenic tumor therapy.

We present a cationic polymer architecture composed of phenylboronic acid (PBA), sugar-installed polyethylenimine (PEI), and polyethylene glycol (PEG). The chemical bonding of PBA with the diol in the sugar enabled the crosslinking of low-molecular-weight (MW) PEI to form high-MW PEI, resulting in strong interaction with anionic DNA for gene delivery. Inside the cell, the binding of PBA and sugar was disrupted by either acidic endosomal pH or intracellular ATP, so gene payloads were released effectively. This dual stimuli-responsive gene release drove the polymer to deliver DNA for high transfection efficiency with low cytotoxicity. In addition, PBA moiety with PEGylation facilitated the binding of polymer/DNA polyplexes to sialylated glycoprotein which is overexpressed on the tumor cell membrane, and thus provided high tumor targeting ability. Therapeutic application of our polymer was demonstrated as an anti-angiogenic gene delivery agent for tumor growth inhibition. Our judicious designed polymer structure based on PBA provides enormous potential as a gene delivery agent for effective gene therapy by stimuli-responsiveness and tumor targeting.

Screening of α-Amylase, α-Glucosidase and Lipase Inhibitory Activity with Gangwon-do Wild Plants Extracts

We investigated α-amylase, α-glucosidase and lipase inhibitory activity of extracts collected from wild plants in Gangwon-do. 90 wild plants were collected and their water and ethanol extracts were obtained. Results of measuring α-amylase inhibitory activity indicated more than 80% of activity inhibition in 10 mg/mL concentration for ethanol extracts of three plants and water extracts of two plants. For α-glucosidase inhibitory activity, ethanol extracts of thirteen plants and water extracts of three plants showed more than 80% of activity inhibition in 10 mg/mL concentration. In the experiment of inhibiting lipase activity, ethanol extracts of seven plants and water extracts of one plants showed above 80% of activity inhibition in 10 mg/mL concentration. These results suggest that the selected extracts could be potentially used as a resource of bioactive materials for health functional foods.

Polydopamine Hollow Nanoparticle Functionalized with N‐diazeniumdiolates as a Nitric Oxide Delivery Carrier for Antibacterial Therapy

A biocompatible nitric oxide (NO) delivery nanoplatform, whose structure is a hollow nanoparticle composed of polydopamine backbone and diazeniumdiolates functional groups, is developed for antibacterial therapy. This platform liberates high NO quantitis and exerts the antibacterial activity with excellent biocompatibility thus being promising for treating bacterial infections.

Therapeutic-Gas-Responsive Hydrogel

Nitric oxide (NO) is a crucial signaling molecule with various functions in physiological systems. Due to its potent biological effect, the preparation of responsive biomaterials upon NO having temporally transient properties is a challenging task. This study represents the first therapeutic-gas (i.e., NO)-responsive hydrogel by incorporating a NO-cleavable crosslinker. The hydrogel is rapidly swollen in response to NO, and not to other gases. Furthermore, the NO-responsive gel is converted to enzyme-responsive gels by cascade reactions from an enzyme to NO production for which the NO precursor is a substrate of the enzyme. The application of the hydrogel as a NO-responsive drug-delivery system is proved here by revealing effective protein drug release by NO infusion, and the hydrogel is also shown to be swollen by the NO secreted from the cultured cells. The NO-responsive hydrogel may prove useful in many applications, for example drug-delivery vehicles, inflammation modulators, and as a tissue scaffold.

Self-assembled nanocomplex between polymerized phenylboronic acid and doxorubicin for efficient tumor-targeted chemotherapy

Since the discovery that nano-scaled particulates can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect, such nanostructures have been exploited as therapeutic small molecule delivery systems. However, the convoluted synthetic process of conventional nanostructures has impeded their feasibility and reproducibility in clinical applications. Herein, we report an easily prepared formulation of self-assembled nanostructures for systemic delivery of the anti-cancer drug doxorubicin (DOX). Phenylboronic acid (PBA) was grafted onto the polymeric backbone of poly(maleic anhydride). pPBA-DOX nanocomplexes were prepared by simple mixing, on the basis of the strong interaction between the 1,3-diol of DOX and the PBA moiety on pPBA. Three nanocomplexes (1, 2, 4) were designed on the basis of [PBA]:[DOX] molar ratios of 1:1, 2:1, and 4:1, respectively, to investigate the function of the residual PBA moiety as a targeting ligand. An acid-labile drug release profile was observed, owing to the intrinsic properties of the phenylboronic ester. Moreover, the tumor-targeting ability of the nanocomplexes was demonstrated, both in vitro by confocal microscopy and in vivo by fluorescence imaging, to be driven by an inherent property of the residual PBA. Ligand competition assays with free PBA pre-treatment demonstrated the targeting effect of the residual PBA from the nanocomplexes 2 and 4. Finally, the nanocomplexes 2 and 4, compared with the free DOX, exhibited significantly greater anti-cancer effects in vitro and even in vivo. Our pPBA-DOX nanocomplex enables a new paradigm for self-assembled nanostructures with potential biomedical applications.

Synthesis and Characterization of Nitric Oxide-Releasing Platinum(IV) Prodrug and Polymeric Micelle Triggered by Light

Herein, we report the proof of concept of photoresponsive chemotherapeutics comprising nitric oxide-releasing platinum prodrugs and polymeric micelles. Photoactivatable nitric oxide-releasing donors were integrated into the axial positions of a platinum(IV) prodrug, and the photolabile hydrophobic groups were grafted in the block copolymers. The hydrophobic interaction between nitric oxide donors and the photolabile groups allowed for the loading of platinum drugs and nitric oxide-releasing donors in the photolabile polymeric micelles. After cellular uptake of micelles, light irradiation induced the release of nitric oxide, which sensitized the cancer cells. Simultaneously, photolabile hydrophobic groups were cleaved from micelles, and the nitric oxide-releasing donor was altered to be more hydrophilic, resulting in the rapid release of platinum(IV) prodrugs. The strategy of using platinum(IV) prodrugs and nitric oxide led to enhanced anticancer effects.

Effective PEI-mediated delivery of CRISPR-Cas9 complex for targeted gene therapy

The-state-of-art CRISPR/Cas9 is one of the most powerful among the approaches being developed to rescue fundamental causes of gene-based inheritable diseases. Several strategies for delivering such genome editing materials have been developed, but the safety, efficacy over time, cost of production, and gene size limitations are still under debate and must be addressed to further improve applications. In this study, we evaluated branched forms of the polyethylenimine (PEI) - branched PEI 25 kDa (BPEI-25K) - and found that it could efficiently deliver CRISPR/Cas9 plasmids. Plasmid DNA expressing both guide RNA and Cas9 to target the Slc26a4 locus was successfully delivered into Neuro2a cells and meditated genome editing within the targeted locus. Our results demonstrated that BPEI-25K is a promising non-viral vector to deliver the CRISPR/Cas9 system in vitro to mediate targeted gene therapy, and these findings contribute to an understanding of CRISPR/Cas9 delivery that may enable development of successful in vivo techniques.