Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a ...protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pah
PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.
Several ocular drug delivery (ODD) systems, like hydrogels, microparticles, nano-emulsions, micro-emulsions, and liposomes have been researched, which can govern the drug release and sustain ...therapeutic levels for a delayed period in the eye. While new drugs targeting methods to the eye are possible by various nanoparticles. Presently in the market, there are fewer choices and need for novel nano-ocular delivery systems as well as therapies for prolonged delivery to the anterior and posterior eye segments. The primary objective of this article is to summarize current discoveries and proven activities of different nano- and microsystems in ODD. This article also depicts some regulatory updates along with the patents granted to the inventor for their work on ODD. Overall, a thought of how the different forthcoming of nanotechnologies like nanoparticles and nanomedicine can be used to investigate the frontiers of ODD and treatment can be withdrawn by this article.
Skin aging is the progressive biological process generally characterized by the appearance of wrinkles, age spots, sagging of skin, and dryness. Since skin is an essential part of physical ...appearance, this has led to increased concerns about skincare. Anti-aging products help in improving the quality and health of the skin by nourishing it. However, due to large particle size they are less efficacious. Nanotechnological approaches for topical anti-aging products have a significant effect on the product performance. Lipidic, polymeric, and metallic nanoparticles have shown potential advantages like enhanced stability and efficacy due to their smaller size. The excipients used in these nanoformulations play an important role in improving the efficacy and shelf-life of the product. The optimal selection of excipients plays a major role in the nanoformulation approach for their enhanced efficacy and stability. For the past three decades the ingredients of natural origin for cosmetic formulations have been widely recognized for being safe and less toxic. The objective of this article is to review the nanoformulations used in anti-aging along with the potential excipients used, currently marketed formulations, and patents filed for cosmetic use. Recent updates related to regulatory aspects of the nanocosmetics have also been highlighted.
Cancer is among the leading causes of mortality and morbidity in the world. Metallic nanoparticles, especially gold nanoparticles (AuNPs) have emerged to be attractive systems to circumvent the ...associated adverse effects. By the virtue of their unique properties of tunable size, shape, composition, optical properties, biocompatibility, minimal toxicity, multivalency, fluorescence-luminescence property and surface plasmon resonance; AuNPs have the potential to be used as drug delivery systems. It is vital to ensure that the drug reaches the target site of action for selective kill of cancer cells without harm to healthy cells. These AuNPs can be easily functionalized with a wide array of ligands like peptides, oligonucleotides, polymers, carbohydrates for active targeting to ensure site specific delivery and reduced systemic effects. AuNPs have been in-vestigated as carriers for gene delivery, drug delivery with or without photothermal therapy, in diagnosis based on radiation or spectroscopy. They have emerged as attractive theranostic approach in the overall management of cancer with superior benefit to risk features. In this review, we have discussed synthesis of different AuNPs (nanorods, spherical nanoparticles, and hollow AuNPs), their functionalization strategies and their applications in biomedical domain. Various research studies and clinical trials on application of AuNPs in diagnosis and therapeutics are highlighted.
Wound management is an unmet therapeutic challenge and a global healthcare burden. Current treatment strategies provide limited efficiency in wound management, thus undergoing constant evolution in ...the treatment approaches. As wound healing is a complex physiological process involving precise synchronization of various phases like hemostasis, inflammation and remodelling, which necessitates innovative treatment strategies. Nanotechnology platforms like polymeric nanofibers (NFs) offer a promising solution for wound management. NFs contain a porous mesh-like structure that mimics the natural extracellular matrix and promote the cell adhesion and proliferation in the wound bed, thus displaying a great potential as a wound healing scaffold. Electrospinning is a simple, versatile and scalable technique for producing highly porous and tuneable NFs with a high surface area. Electrospun NFs are presenting extensive application in wound management, especially for burns and diabetic foot ulcers. This review briefly discusses the wound physiology and conventional treatment strategies. It also provides an overview of the electrospinning process and its principle, highlighting the application of electrospun polymeric NFs in wound management. The authors have made an attempt to emphasizes on the clinical challenges and future perspectives along with regulatory aspects of NFs as a wound dressing.
The aim of the present research was to develop a bilayer tablet of venlafaxine hydrochloride for bimodal drug release. In the present investigation authors have tried to explore fenugreek mucilage ...(FNM) for bioadhesive sustained release layer. The attempt has been made to combine FNM with well studied bioadhesive polymers like hydroxy propyl methyl cellulose (HPMC), Carbopol, and Xanthan Gum. The formulations were evaluated for swelling Index, ex vivo bioadhesion, water uptake studies, in vitro drug release and dissolution kinetics was studied. Substantial bioadhesion force (2.4 ± 0.023 g) and tablet adhesion retention time (24 ± 2 h) was observed with FNM and HPMC combination at 80:20 ratio. The dissolution kinetics followed the Higuchi model (R (2) = 0.9913) via a non-Fickian diffusion controlled release mechanism after the initial burst. The 3(2) full factorial design was employed in the present study. The type of polymers used in combination with FNM (X1) and percent polymer replaced with FNM (X2) were taken as independent formulations variables. The selected responses, bioadhesion force (0.11-0.25 ± 0.023 g), amount of drug released in 10 h, Y10 (78.20-95.78 ± 1.24%) and bioadhesive strength, (19-24 ± 2 h) presented good correlation with the selected independent variables. Statistical analysis (ANOVA) of the optimized bilayer formulations showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05) in the amount of drug released after 1 hr till 12 h from optimized formulations was observed. The natural mucilage like FNM could be successfully incorporated into tablet with only 20% replacement with HPMC and it showed good bioadhesiveness and sustained drug release.
Ocular in situ gel (ISG) is a promising alternative to alleviate the shortcomings of conventional formulations due to their association with dose accuracy and effective administration with prolonged ...contact time. Therefore, present research aimed to develop a thermo-responsive in situ gel (TRISG) for ocular drug delivery (ODD) with different levels of Pluronic® F407 and Pluronic® F188 for ciprofloxacin HCl (CFH) and olopatadine HCl (OLH). The three optimal formulations were selected based on the physicochemical characterization of nine batches and were evaluated successfully. The batch F5 of CFHOLH-TRISG explored the remarkable outcomes within acceptable limits in aspects of physicochemical characterization and other parameters. The TRISG has proven to release over 120 min, which was more significant than conventional drops (60 min), suggesting sustained release and better corneal penetration. A compressive finding explored the TRISG with combination might be a pragmatic choice for ODD with effective administration, enhanced ocular bioavailability, and sustained release.
A reverse phase chromatography technique to simultaneously estimate ciprofloxacin HCl and olopatadine HCl as bulk drugs and in formulation has been developed. The chromatographic separation of drugs ...and formulation was accomplished on C18 Agilent Zorbax column (250 x 4.6 mm, 5 µm) using acetonitrile: TFA water (40:60, V/V). A 10 µL volume was injected with flow rate 1 mL min-1, and peaks were detected. The retention periods for ciprofloxacin HCl and olopatadine HCl were 2.92 and 5.10 minutes respectively. The method was linear in the concentration ranges 24-36 µg mL-1 and 56- 84 µg mL-1 for ciprofloxacin HCl and olopatadine HCl, with regression coefficient correlation values of 0.9999 and 0.9996, respectively. Relative standard deviation of precision, accuracy, and ruggedness was below 2 %. Forced degradation studies were performed under different conditions which were in an admissible range. The established method was simple, accurate, and precise. Therefore, it can be applied for the routine quantification and degradation of these drugs and formulation.
Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a ...versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.
In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. ...As a treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic's Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic product trans-cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618.
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