Search for: All records

Abstract Nanoparticles of zeolitic imidazole framework‐8 (ZIF‐8 NPs), which are the subclass of metal‐organic frameworks consisting of Zn ion and 2‐methylimidazole, have been identified as promising drug carriers since their large microporous structure is suited for encapsulating hydrophobic drug molecules. However, one of the limitations of ZIF‐8 NPs is their low stability in physiological solutions, especially in the presence of water and phosphate anions. These molecules can interact with the coordinatively unsaturated Zn sites at the external surface to induce the degradation of ZIF‐8 NPs. In this study, herein a facile approach is reported to enhance the chemical stability of ZIF‐8 NPs by surface coating with polyacrylic acid (PAA). The PAA‐coated ZIF‐8 (PAA‐ZIF‐8) NPs are prepared by mixing ZIF‐8 NPs and PAA in water. PAA coating inhibits the degradation of ZIF‐8 NPs in water as well as phosphate‐buffered saline over 6 days, which seems to be due to the coordination of carboxyl groups of PAA to the reactive Zn sites. Furthermore, the PAA‐ZIF‐8 NPs loaded with the anticancer drug doxorubicin (Dox) show cytotoxicity in human colon cancer cells. These results clearly show the feasibility of the PAA coating approach to improve the chemical stability of ZIF‐8 NPs without impairing their drug delivery capability. 

Abstract Thermogels that exhibit a sol‐gel transition at body temperature represent a promising class of injectable biomaterials for biomedical applications. Thermogels reported thus far are generally composed of amphiphilic block copolymer micelles with an isotropic thermosensitive surface that induces intermicellar aggregation upon heating. Despite the promise, these hydrogels exhibit low mechanical strengths due to their uncontrollable aggregation resulting in void formation. To gain better control over intermicellar assembly, herein a novel thermogel design concept is presented based on patchy polymeric micelles bearing multiple thermosensitive surface domains. These domains serve as “patches” to bridge the micelles to form a percolated network structure. Patchy micelles are prepared from a binary mixture of amphiphilic block copolymers: Poly(N‐acryloylmorpholine)‐b‐poly(N‐benzylacrylamide) (PAM‐PBzAM) and poly (N‐isopropyl acrylamide)‐b‐poly(N‐benzylacrylamide) (PNIPAM‐PBzAM), where PBzAM, PAM and PNIPAM are the hydrophobic, hydrophilic and thermosensitive blocks, respectively. At 25 °C, the polymers self‐assembled into mixed shell micelles having a phase‐separated shell with PAM‐ and PNIPAM‐rich domains. At 37 °C, the PNIPAM domains undergo a hydrophilic‐to‐hydrophobic transition to induce intermicellar assembly into entangled worm‐like structures resulting in hydrogel formation. Patchy micelles form a homogeneous network structure without voids. The micelle design significantly affects the inter‐micellar assembly, the thermogelling behavior, and the mechanical properties of the hydrogels. 

Abstract Per/polysulfide species that are generated from endogenously produced hydrogen sulfide have critical regulatory roles in a wide range of cellular processes. However, the lack of delivery systems that enable controlled and sustained release of these unstable species in biological systems hinders the advancement of sulfide biology research, as well as the translation of knowledge to therapeutic applications. Here, a novel approach is developed to generate per/polysulfide species in cells by combining an H₂S donor and manganese porphyrin‐containing polymeric micelles (MnPMCs) that catalyze oxidization of H₂S to per/polysulfide species. MnPMCs serve as a catalyst for H₂S oxidation in aerobic phosphate buffer. HPLC‐MS/MS analysis reveals that H₂S oxidation by MnPMCs in the presence of glutathione results in the formation of glutathione‐SnH (n= 2 and 3). Furthermore, co‐treatment of human umbilical vein endothelial cells with the H₂S donor anethole dithiolethione and MnPMCs increases intracellular per/polysulfide levels and induces a proangiogenic response. Co‐delivery of MnPMCs and an H₂S donor is a promising approach for controlled delivery of polysulfides for therapeutic applications. 

Abstract Gaseous signaling molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) have recently been recognized as essential signal mediators that regulate diverse physiological and pathological processes in the human body. With the evolution of gaseous signaling molecule biology, their therapeutic applications have attracted growing attention. One of the challenges in translational research of gaseous signaling molecules is the lack of efficient and safe delivery systems. To tackle this issue, researchers developed a library of gas donors, which are low molecular weight compounds that can release gaseous signaling molecules upon decomposition under physiological conditions. Despite the significant efforts to control gaseous signaling molecule release from gas donors, the therapeutic potential of gaseous signaling molecules cannot be fully explored due to their unfavorable pharmacokinetics and toxic side effects. Recently, the use of nanoparticle‐based gas donors, especially self‐assembled polymeric gas donors, have emerged as a promising approach. In this review, we describe the development of conventional small gas donors and the challenges in their therapeutic applications. We then illustrate the concepts and critical aspects for designing self‐assembled polymeric gas donors and discuss the advantages of this approach in gasotransmistter delivery. We also highlight recent efforts to develop the delivery systems for those molecules based on self‐assembled polymeric nanostructures. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging Technologies 

Abstract Hydrogen sulfide (H₂S) is a gaseous signaling molecule in the human body and has attracted attention in cancer therapy due to its regulatory roles in cancer cell proliferation and migration. Accumulating evidence suggests that continuous delivery of H₂S to cancer cells for extended periods of time suppresses cancer progression. However, one major challenge in therapeutic applications of H₂S is its controlled delivery. To solve this problem, polymeric micelles are developed containing H₂S donating‐anethole dithiolethione (ADT) groups, with H₂S release profiles optimal for suppressing cancer cell proliferation. The micelles release H₂S upon oxidation by reactive oxygens species (ROS) that are present inside the cells. The H₂S release profiles can be controlled by changing the polymer design. Furthermore, the micelles that show a moderate H₂S release rate exert the strongest anti‐proliferative effect in human colon cancer cells in in vitro assays as well as the chick chorioallantoic membrane cancer model, while the micelles do not affect proliferation of human umbilical vein endothelial cells. This study shows the importance of fine‐tuning H₂S release profiles using a micelle approach for realizing the full therapeutic potential of H₂S in cancer treatment. 

Polymeric nanoparticles with reactive functional groups are an attractive platform for drug carriers that can be conjugated with drugs through a cleavable covalent linkage. Since the required functional groups vary depending on the drug molecule, there is a need for development of a novel post-modification method to introduce different functional groups to polymeric nanoparticles. We recently reported phenylboronic acid (PBA)-containing nanoparticles (BNP) with a unique framboidal morphology created via one-step aqueous dispersion polymerization. Since BNPs have high surface area due to their framboidal morphology and contain a high density of PBA groups, these particles can be used as nanocarriers for drugs that can bind to PBA groups such as curcumin and a catechol-bearing carbon monoxide donor. To further explore the potential of BNPs, in this article we report a novel strategy to introduce different functional groups to BNPs via the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction between the PBA groups and iodo- and bromo-coupling partners. We developed a new catalytic system that efficiently catalyzes Suzuki–Miyaura reactions in water without the need for an organic solvent, as confirmed by NMR. Using this catalyst system, we show that BNPs can be functionalized with carboxylic acids, aldehyde, and hydrazide groups while keeping their original framboidal morphology as confirmed via IR, alizarin red assay, and TEM. Furthermore, the potential of the functionalized BNP in drug delivery applications was demonstrated by conjugating the hydrogen sulfide (H2S)-releasing compound anethole dithiolone to carboxylic acid-functionalized BNPs and show their H2S-releasing capability in cell lysate.