Solid Dispersion Incorporated into Dissolving Microneedles for Improved Antifungal Activity of Amphotericin B: In Vivo Study in a Fungal Keratitis Model

Article

作者: Domínguez-Robles, Juan ; Permana, Andi Dian ; Andi, Maqhfirah Nurul Fitri ; Pamornpathomkul, Boonnada ; Akram, Muhammad ; Saputra, Mesakh Diki ; Himawan, Achmad ; Syahirah, Nor Atikah ; Mahfud, Muhammad Alif Sya'ban ; Elim, Diany ; Mahfufah, Ulfah ; Mir, Maria ; Sultan, Nurul Aisha Fitri

Fungal keratitis (FK) is a fungal infection of the cornea, which is part of the eye and causes corneal ulcers and an increased risk of permanent blindness, which is often found in Candida albicans species. Amphotericin B (AMB), which is a group of polyenes as the first-line treatment of FK, is effective in annihilating C. albicans. However, AMB preparations such as eye drops and ointments have major drawbacks, for instance, requiring more frequent administrations, loss of the drug by the drainage process, and rapid elimination in the precornea, which result in low bioavailability of the drug. An ocular dissolving microneedle containing the solid dispersion amphotericin B (DMN-SD-AMB) had been developed using a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers, while the solid dispersion AMB (SD-AMB) was contained in the needle as a drug. This study aims to determine the most optimal and safest DMN-SD-AMB formula for the treatment of FK in the eye as well as a solution to overcome the low bioavailability of AMB eye drops and ointment preparations. SD-AMB had been successfully developed, which was characterized by increased antifungal activity and drug release in vitro compared to other treatments. Furthermore, DMN-SD-AMB studies had also been successfully performed with the best formulation, which exhibited the best ex vivo corneal permeation profile and antifungal activity as well as being safe from eye irritation. In addition, an in vivo antifungal activity using a rabbit infection model shows that the number of fungal colonies was 0.98 ± 0.11 log₁₀ CFU/mL (F3), 5.76 ± 0.32 log₁₀ CFU/mL (AMB eye drops), 4.01 ± 0.28 log₁₀ CFU/mL (AMB ointments), and 9.09 ± 0.65 log₁₀ CFU/mL (control), which differed significantly (p < 0.05). All of these results evidence that DMN-SD-AMB is a new approach to developing intraocular preparations for the treatment of FK.

2020-12-01·Talanta2区 · 化学

Exploration of synthesizing fluorescent silicon nanoparticles and label-free detection of sulfadiazine sodium

2区 · 化学

Article

作者: Bai, Yunfeng ; Yang, Xiaoming ; Feng, Feng ; Su, Qian ; Xiao, Jimei

Herein, silica nanoparticles (SiNPs) with blue-fluorescence have been originally synthesized through one facile hydrothermal way, and this kind of SiNPs were water-soluble with the relative quantum yield of around 6%. Meanwhile, N-(triethoxysilylpropyl) urea severed as the silica source, while potassium hydrogen phthalate as the doping reagent. Also, SiNPs exhibited the acceptable stability and excitation-dependent fluorescence property. Moreover, their surfaces of the obtained SiNPs were equipped with multiple functional groups including -Si-O-Si-, -Si-H, -COOH, -NH₂ and -OH. Importantly, the fluorescence of SiNPs could be specifically quenched by sulfadiazine sodium (SD-Na), thus achieving a label-free detection of SD-Na, which displayed a wide linear response in the range of 0.8 μM-800 μM with a detection limit of 1.02 μM. Additionally, we explored the mechanism of SiNPs sensing SD-Na on the basis of aggregation-induced quenching. To be specific, the particle size of SiNPs increased from 29.9 nm to 203.7 nm induced by the electrostatic interactions between SiNPs and SD-Na, which was further confirmed by high resolution transmission electron microscopy. Consequently, the proposed strategy here broadened the ways of assaying sulfadiazine sodium.

2017-01-09·Nucleic acids research2区 · 生物学

Visualization of self-delivering hydrophobically modified siRNA cellular internalization

2区 · 生物学

ArticleOA

作者: Pandarinathan, Lakshmipathi ; Didiot, Marie-Cécile ; Corvera, Silvia ; Prot, Matthieu ; Khvorova, Anastasia ; Navaroli, Deanna M ; Ly, Socheata ; Echeverria, Dimas ; Lifshitz, Lawrence M ; Alterman, Julia F ; Standley, Clive ; Bellve, Karl D ; Cardia, James ; Fogarty, Kevin

siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of asymmetric, chemically stabilized, cholesterol-modified siRNAs (sd-rxRNAs^®) that efficiently enter cells and tissues without the need for formulation. We demonstrate that uptake is rapid with significant membrane association within minutes of exposure followed by the formation of vesicular structures and internalization. Furthermore, sd-rxRNAs are internalized by a specific class of early endosomes and show preferential association with epidermal growth factor (EGF) but not transferrin (Tf) trafficking pathways as shown by live cell TIRF and structured illumination microscopy (SIM). In fixed cells, we observe ∼25% of sd-rxRNA co-localizing with EGF and <5% with Tf, which is indicative of selective endosomal sorting. Likewise, preferential sd-rxRNA co-localization was demonstrated with EEA1 but not RBSN-containing endosomes, consistent with preferential EGF-like trafficking through EEA1-containing endosomes. sd-rxRNA cellular uptake is a two-step process, with rapid membrane association followed by internalization through a selective, saturable subset of the endocytic process. However, the mechanistic role of EEA1 is not yet known. This method of visualization can be used to better understand the kinetics and mechanisms of hydrophobic siRNA cellular uptake and will assist in further optimization of these types of compounds for therapeutic intervention.

项与 Anti-CTFG RNAi therapy(Phio Pharmaceuticals Corp.) 相关的新闻（医药）

2021-06-08

·BioSpace

BioAxone BioSciences Announces Notice of Allowance for Self-Delivering RNA Interference for the Treatment of Spinal Cord Injury

Issued claims relate to transient PTEN suppression for nerve regeneration BOSTON--(BUSINESS WIRE)-- BioAxone BioSciences, Inc., a biotechnology company applying an innovative understanding of axon regeneration and neuronal signaling to transform the lives of patients afflicted with neurotrauma or neurovascular disorders, today announced that it has received a Notice of Allowance from the United States Patent and Trademark Office (USPTO). The notice covers the critical patent application (US 16/321,229) for the proprietary method of treatment of spinal cord injury with BA-434, a novel sd-rxRNA compound that targets transient, non-permanent PTEN suppression to promote axon regeneration and reduce paralysis. Scientists have provided evidence that suppression of the protein PTEN is one of the most robust targets to promote regeneration of damaged axons. PTEN is also important in surveillance and defense against unwanted cell growth, including protection from cancer. However, until now the development of inhibitors to promote axon regeneration have focused on methods that permanently silence PTEN. “BA-434 is a therapeutically relevant drug candidate that overcomes the challenge of other PTEN inhibitors which deliver permanent suppression,“ said Lisa McKerracher, PhD, CEO, BioAxone BioSciences. “Our drug candidate delivers transient PTEN suppression that is robust in the model systems used in preclinical testing. We look forward to continued exploration of the opportunity to allow for axon regeneration to help serve this unmet need of patients with spinal cord injury.” BA-434 is BioAxone’s novel self-delivering RNA interference compound that reduces expression of PTEN, a protein that blocks axon regeneration in adult neurons. Research for development of BA-434 was supported by NIH Small Business Innovation Research grants. About BioAxone BioSciences, Inc. Based in Boston, BioAxone BioSciences is applying its deep understanding of axon regeneration and neuronal signaling pathways to transform the lives of patients afflicted with neurotrauma or neurovascular disorders. Leveraging 20 years of pioneering research in axon regeneration and diseases involving Rho/ROCK signaling, BioAxone has a clinical stage drug (BA-210) and a preclinical program (BA-434) targeting axon regeneration for treatment of spinal cord injury. BA-1049, intended for license, is the lead orally-available ROCK2 inhibitor to restore endothelial cell barrier function in cavernous angioma (CA) and cerebral aneurysms. Cavernous angioma, which has both spontaneous and genetic forms, and cerebral aneurysms, are considered unmet medical needs with no pharmacological treatment options currently available for patients. For more information, visit .

100 项与 Anti-CTFG RNAi therapy(Phio Pharmaceuticals Corp.) 相关的药物交易

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