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 ; Mahfufah, Ulfah ; Elim, Diany ; 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 ; Su, Qian ; Feng, Feng ; 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: Didiot, Marie-Cécile ; Pandarinathan, Lakshmipathi ; Corvera, Silvia ; Prot, Matthieu ; Khvorova, Anastasia ; Navaroli, Deanna M ; Echeverria, Dimas ; Ly, Socheata ; 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）

2023-05-24

·BioSpace

Phio Pharmaceuticals Announces Initiation of Collaborative Clinical Trial with PH-762, AgonOx's Tumor Infiltrating Lymphocyte Program (AGX148) and Providence Cancer Institute

One of two newly announced clinical trials for its lead product candidate, PH-762 MARLBOROUGH, Mass., May 24, 2023 /PRNewswire/ -- Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL™ RNAi platform technology is designed to make immune cells more effective in killing tumor cells, today announced its clinical development partner, AgonOx, Inc, in collaboration with Providence Cancer Institute, has completed the site initiation visit and can commence with patient accrual. The clinical trial will assess the safety and the potential for enhanced therapeutic benefit from the administration of Phio's PH-762 treated 'double positive' (DP) CD8 tumor infiltrating lymphocytes (TILs) in patients with melanoma and other advanced solid tumors. The trial will be conducted at Providence Cancer Institute in Portland, Oregon, by Principal Investigator Brendan Curti, MD, Medical Oncologist and Robert W. Franz Endowed Chair for Clinical Research at the Earle A. Chiles Research Institute, a division of Providence. "With both regulatory clearance and the completion of the site initiation visit this study can now proceed and we are excited to test PH-762 combined with this new TIL therapy," said Andrew Weinberg, PhD, President and CSO at AgonOx and Member at the Earle A. Chiles Research Institute, Providence Cancer Institute. "With the initiation of this clinical trial, Phio continues to advance the development of improved cell therapies for oncologic indications. We are pleased with our ongoing collaboration with AgonOx and the Providence Cancer Institute and look forward to continued progress," said Robert Bitterman, Phio's President and CEO. Phio recently received FDA clearance to initiate a clinical trial of intratumoral PH-762 in patients with cutaneous squamous cell carcinoma, melanoma, and Merkel cell carcinoma. The trial is expected to commence in the second half of 2023. About Phio Pharmaceuticals Corp. Phio Pharmaceuticals Corp. (Nasdaq: PHIO) is a clinical stage biotechnology company whose proprietary INTASYL™ RNAi technology is designed to make immune cells more effective in killing tumor cells. INTASYL is the only self-delivering RNAi technology focused on immuno-oncology therapeutics. INTASYL drugs precisely target specific proteins that reduce the body's ability to fight cancer, without the need for specialized formulations or drug delivery systems. For additional information, visit the Company's website, . About AgonOx, Inc. AgonOx, Inc. is a privately held, Portland, OR-based biotechnology company. The company was the first to identify and expand tumor-reactive T cells using CD39 and CD103 (DP) CD8s. A patented process that can also be used to identify tumor-reactive TCRs. Agonox is also developing a pipeline of novel immunotherapy drugs targeting key regulators of the immune response to cancer. For additional information, visit the company's website, . About Providence Cancer Institute of Oregon Providence Cancer Institute of Oregon, a part of Providence St. Joseph Health, offers the latest in cancer services, including diagnosis, treatment, prevention, education and support. Providence is home to the Earle A. Chiles Research Institute, an internationally renowned leader in the field of cancer immunotherapy since 1993, where investigators lead more than 400 active clinical trials for cancers of the breast, colon, prostate, lung, esophagus, liver, pancreas, head and neck, ovary, skin, blood and other conditions. Learn more at Providence.org/ORcancer. Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as "intends," "believes," "anticipates," "indicates," "plans," "expects," "suggests," "may," "would," "should," "potential," "designed to," "will," "ongoing," "estimate," "forecast," "target," "predict," "could" and similar references, although not all forward-looking statements contain these words. These statements are based only on our current beliefs, expectations and assumptions and are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Examples of forward-looking statements include statements regarding the potential for enhanced therapeutic benefit from the administration of PH-762 treated DP TIL and the timing of the commencement of our anticipated Phase 1b clinical trial of PH-762 in cutaneous squamous cell carcinoma, melanoma and Merkel cell carcinoma. Our actual results may differ materially from those indicated in the forward-looking statements as a result of a number of important factors, including, but not limited to, the impact to our business and operations by inflationary pressures, rising interest rates, recession fears, the development of our product candidates, results from our preclinical and clinical activities, our ability to execute on business strategies, our ability to develop our product candidates with collaboration partners, and the success of any such collaborations, the timeline and duration for advancing our product candidates into clinical development, the timing or likelihood of regulatory filings and approvals, the success of our efforts to commercialize our product candidates if approved, our ability to manufacture and supply our product candidates for clinical activities, and for commercial use if approved, the scope of protection we are able to establish and maintain for intellectual property rights covering our technology platform, our ability to obtain future financing, market and other conditions and those identified in our Annual Report on Form 10-K under the caption "Risk Factors" and in other filings the Company periodically makes with the SEC. Readers are urged to review these risk factors and to not act in reliance on any forward-looking statements, as actual results may differ from those contemplated by our forward-looking statements. Phio does not undertake to update forward-looking statements to reflect a change in its views, events or circumstances that occur after the date of this release, except as required by law. Company Codes: NASDAQ-NMS:PHIO

免疫疗法临床1期临床申请

2023-05-17

·PipelineReview

Phio Pharmaceuticals Announces FDA Clearance to Initiate Clinical Trial of PH-762 for Treatment of Skin Carcinomas

MARLBOROUGH, MA, USA I May 16, 2023 I Phio Pharmaceuticals Corp. (Nasdaq: PHIO ), a clinical stage biotechnology company whose proprietary INTASYL ™ RNAi platform technology is designed to make immune cells more effective in killing tumor cells, today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company's Investigational New Drug (IND) application to proceed with a clinical trial of Phio's lead product candidate, PH-762. PH-762 is an INTASYL compound that reduces the expression of PD-1, a protein that inhibits T cells' ability to kill cancer cells. Phio plans to initiate its Phase 1b clinical trial of intratumoral PH-762 in patients with cutaneous squamous cell carcinoma, melanoma and Merkel cell in the second half of 2023. "The clearance of our IND application for PH-762 represents a significant milestone in Phio's continued evolution from drug discovery to clinical development," said Phio's President and CEO, Robert Bitterman. Dr. Mary Spellman, Acting Chief Medical Officer, added, "Cutaneous malignancies may be both locally destructive and systemically devastating. We look forward to investigating this new immuno-oncology approach to treat these carcinomas." The initial multi-center, dose-escalating, Phase 1b clinical trial under Phio's cleared IND is designed to evaluate the safety and tolerability of neoadjuvant use of intratumorally injected PH-762, assess the tumor response, and determine the dose or dose range for continued study of PH-762. Phio will focus its efforts on the U.S. clinical trial and intends to wind down its first-in-human clinical trial for PH-762 in France, which was limited to the treatment of patients with metastatic melanoma. PH-762 has also received clearance to proceed under an IND sponsored by AgonOx, Inc. in a clinical trial evaluating PH-762 treated "double positive" (DP) CD8 tumor infiltrating lymphocytes (TIL) in patients with melanoma and other advanced solid tumors. About Phio Pharmaceuticals Corp. Phio Pharmaceuticals Corp. (Nasdaq: PHIO ) is a clinical stage biotechnology company whose proprietary INTASYL ™ RNAi technology is designed to make immune cells more effective in killing tumor cells. INTASYL is the only self-delivering RNAi technology focused on immuno-oncology therapeutics. INTASYL drugs precisely target specific proteins that reduce the body's ability to fight cancer, without the need for specialized formulations or drug delivery systems. For additional information, visit the Company's website, www.phiopharma.com . SOURCE: Phio Pharmaceuticals

临床申请临床1期免疫疗法

2023-05-16

·BioSpace

Phio Pharmaceuticals Announces FDA Clearance to Initiate Clinical Trial of PH-762 for Treatment of Skin Carcinomas

MARLBOROUGH, Mass., May 16, 2023 /PRNewswire/ -- Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL™ RNAi platform technology is designed to make immune cells more effective in killing tumor cells, today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company's Investigational New Drug (IND) application to proceed with a clinical trial of Phio's lead product candidate, PH-762. PH-762 is an INTASYL compound that reduces the expression of PD-1, a protein that inhibits T cells' ability to kill cancer cells. Phio plans to initiate its Phase 1b clinical trial of intratumoral PH-762 in patients with cutaneous squamous cell carcinoma, melanoma and Merkel cell in the second half of 2023. Logo - "The clearance of our IND application for PH-762 represents a significant milestone in Phio's continued evolution from drug discovery to clinical development," said Phio's President and CEO, Robert Bitterman. Dr. Mary Spellman, Acting Chief Medical Officer, added, "Cutaneous malignancies may be both locally destructive and systemically devastating. We look forward to investigating this new immuno-oncology approach to treat these carcinomas." The initial multi-center, dose-escalating, Phase 1b clinical trial under Phio's cleared IND is designed to evaluate the safety and tolerability of neoadjuvant use of intratumorally injected PH-762, assess the tumor response, and determine the dose or dose range for continued study of PH-762. Phio will focus its efforts on the U.S. clinical trial and intends to wind down its first-in-human clinical trial for PH-762 in France, which was limited to the treatment of patients with metastatic melanoma. PH-762 has also received clearance to proceed under an IND sponsored by AgonOx, Inc. in a clinical trial evaluating PH-762 treated "double positive" (DP) CD8 tumor infiltrating lymphocytes (TIL) in patients with melanoma and other advanced solid tumors. About Phio Pharmaceuticals Corp. Phio Pharmaceuticals Corp. (Nasdaq: PHIO) is a clinical stage biotechnology company whose proprietary INTASYL™ RNAi technology is designed to make immune cells more effective in killing tumor cells. INTASYL is the only self-delivering RNAi technology focused on immuno-oncology therapeutics. INTASYL drugs precisely target specific proteins that reduce the body's ability to fight cancer, without the need for specialized formulations or drug delivery systems. For additional information, visit the Company's website, . Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as "intends," "believes," "anticipates," "indicates," "plans," "expects," "suggests," "may," "would," "should," "potential," "designed to," "will," "ongoing," "estimate," "forecast," "target," "predict," "could" and similar references, although not all forward-looking statements contain these words. These statements are based only on our current beliefs, expectations and assumptions and are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Examples of forward-looking statements include statements regarding the timing of the commencement of our anticipated Phase 1b clinical trial of PH-762 in cutaneous squamous cell carcinoma, melanoma and Merkel cell, proceeding with the AgonOx, Inc.-sponsored clinical trial and our expected wind-down of our first-in-human clinical trial for PH-762 in France. Our actual results may differ materially from those indicated in the forward-looking statements as a result of a number of important factors, including, but not limited to, the impact to our business and operations by inflationary pressures, rising interest rates, recession fears, the development of our product candidates, results from our preclinical and clinical activities, our ability to execute on business strategies, our ability to develop our product candidates with collaboration partners, and the success of any such collaborations, the timeline and duration for advancing our product candidates into clinical development, the timing or likelihood of regulatory filings and approvals, the success of our efforts to commercialize our product candidates if approved, our ability to manufacture and supply our product candidates for clinical activities, and for commercial use if approved, the scope of protection we are able to establish and maintain for intellectual property rights covering our technology platform, our ability to obtain future financing, market and other conditions and those identified in our most recent Annual Report on Form 10-K under the caption "Risk Factors" and in other filings the Company periodically makes with the SEC. Readers are urged to review these risk factors and to not act in reliance on any forward-looking statements, as actual results may differ from those contemplated by our forward-looking statements. Phio does not undertake to update forward-looking statements to reflect a change in its views, events or circumstances that occur after the date of this release, except as required by law. Contact Phio Pharmaceuticals Corp. ir@phiopharma.com Investor Contact Ashley R. Robinson LifeSci Advisors arr@lifesciadvisors.com Company Codes: NASDAQ-NMS:PHIO

临床申请临床1期免疫疗法

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

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