Tunable Release Profiles Research Articles

Ethoxy Acetalated Dextran-Based Biomaterials for Therapeutic Applications.

A novel class of pH-responsive polymers, acetalated dextran, has emerged in the field of biomaterials. These versatile materials are derived from dextran through a simple acetalation reaction, allowing for the creation of polymers with a tunable release profile which allows the controlled release of encapsulated therapeutics in response to acidic environments. Despite their recent introduction, acetalated dextran has rapidly garnered significant interest due to its potential for various therapeutic applications. This review delves specifically into the recent advancements of ethoxy acetalated dextran or Ace-DEX, a particular acetalated dextran with a distinct advantage: its degradation products (acetone and ethanol) are less toxic compared to other variants that produce methanol. The focus of this review is the diverse range of biomedical applications currently being explored for Ace-DEX-based scaffolds. Finally, this review concludes by addressing the existing challenges associated with Ace-DEX and outlining potential future research directions within this promising field.

Hydroxypropyl methylcellulose phthalate films reinforced with nanocrystalline cassava starch and intended its applications for colonic drug delivery

Controlled-release drug delivery systems are crucial for improving therapeutic efficacy and patient compliance. Hydroxypropyl methylcellulose phthalate (HPMCP) films are promising candidates due to their film-forming properties and tunable release profiles. However, their mechanical properties can limit their applicability. This study aimed to assess the effect of addition of nanocrystalline cassava (NCS) starches to HPMCP films on the physicochemical and mechanical properties and the ability of films to control drug release rate. Reinforced HPMCP films with 2, 4 and 6 % w/w of NCS were characterized as a function of the microstructure, X-ray diffraction pattern, mechanical properties, and dissolution property. It was found that increasing starch amount induced an increase in heterogeneity of the film microstructure and crystallinity. The tensile strength of HPMCP films increased with addition of starches, while the elongation at break decreased. The lowest dissolution in pH 6.8 phosphate buffer solution was found for films containing NCS at 2 and 4 % w/w. For the application purposes, HPMCP containing different amounts of NCS was used to coat over diclofenac sodium tablets. The tablets coated with HPMCP containing 4 % w/w NCS showed the lowest drug release of 73.5 % in pH 6.8 phosphate buffer solution at 240 min. According to our results, the addition of NCS at adequate amount allowed to improve the mechanical properties of HPMCP films and to decrease the drug release rate which is important for the site-specific drug delivery process.

Injectable hydrogel based on liposome self-assembly for controlled release of small hydrophilic molecules

Controlled release of low molecular weight hydrophilic drugs, administered locally, allows maintenance of high concentrations at the target site, reduces systemic side effects, and improves patient compliance. Injectable hydrogels are commonly used as a vehicle. However, slow release of low molecular weight hydrophilic drugs is very difficult to achieve, mainly due to a rapid diffusion of the drug out of the drug delivery system. Here we present an injectable and self-healing hydrogel based entirely on the self-assembly of liposomes. Gelation of liposomes, without damaging their structural integrity, was induced by modifying the cholesterol content and surface charge. The small hydrophilic molecule, sodium fluorescein, was loaded either within the extra-liposomal space or encapsulated into the aqueous cores of the liposomes. This encapsulation strategy enabled the achievement of controlled and adjustable release profiles, dependent on the mechanical strength of the gel. The hydrogel had a high mechanical strength, minimal swelling, and slow degradation. The liposome-based hydrogel had prolonged mechanical stability in vivo with benign tissue reaction. This work presents a new class of injectable hydrogel that holds promise as a versatile drug delivery system. Statement of significanceThe porous nature of hydrogels poses a challenge for delivering small hydrophilic drug, often resulting in initial burst release and shorten duration of release. This issue is particularly pronounced with physically crosslinked hydrogels, since their matrix can swell and dissipate rapidly, but even in cases where the polymers in the hydrogel are covalently cross-linked, small molecules can be rapidly released through its porous mesh. Here we present an injectable self-healing hydrogel based entirely on the self-assembly of liposomes. Small hydrophilic molecules were entrapped inside the extra-liposomal space or loaded into the aqueous cores of the liposomes, allowing controlled and tunable release profiles.

High-yield fabrication of monodisperse multilayer nanofibrous microparticles for advanced oral drug delivery applications

Recent advances in the use of nano- and microparticles in drug delivery, cell therapy, and tissue engineering have led to increasing attention towards nanostructured microparticulate formulations for maximum benefit from both nano- and micron sized features. Scalable manufacturing of monodisperse nanostructured microparticles with tunable size, shape, content, and release rate remains a big challenge. Current technology, mainly comprises complex multi-step chemical procedures with limited control over these aspects. Here, we demonstrate a novel technique for high-yield fabrication of monodisperse monolayer and multilayer nanofibrous microparticles (MoNami and MuNaMi respectively). The fabrication procedure includes sequential electrospinning followed by micro-cutting at room temperature and transfer of particles for collection. The big advantage of the introduced technique is the potential to apply several polymer-drug combinations forming multilayer microparticles enjoying extracellular matrix (ECM)-mimicking architecture with tunable release profile. We demonstrate the fabrication and study the factors affecting the final three-dimensional structure. A model drug is encapsulated into a three-layer sheet (PLGA-pullulan-PLGA), and we demonstrate how the release profile changes from burst to sustain by simply cutting particles out of the electrospun sheet. We believe our fabrication method offers a unique and facile platform for realizing advanced microparticles for oral drug delivery applications.

Orthogonal Self-Assembly of Amphiphilic Peptide Hydrogels and Liposomes Results in Composite Materials with Tunable Release Profiles.

Self-assembled nanomaterials are promising candidates for drug delivery by providing a higher degree of spatiotemporal control compared to free drugs. However, challenges such as burst release, inadequate targeting, and drug-nanomaterial incompatibility leave room for improvement. The combination of orthogonal self-assembling systems can result in more useful materials that improve upon these weaknesses. In this work, we investigate an orthogonal self-assembling system of nanofibrous MultiDomain Peptide (MDP) hydrogels encapsulating liposomes. Both positively charged and negatively charged MDPs were prepared and mixed with positively charged, negatively charged, or zwitterionic liposomes for a total of six composites. We demonstrate that, despite both systems being amphiphilic, they are able to mix while retaining their independent identities. We show that changing the charge of either liposomes or MDPs does not hinder the self-assembly of either system or significantly affect their rheological properties. In all six cases, small molecules encapsulated in liposome-MDP composites resulted in slower release than was possible in MDP hydrogels alone. However, in one case, positively charged MDPs destabilized negatively charged liposomes and resulted in a unique release profile. Finally, we show that MDP hydrogels substantially decrease the release of chemotherapeutic doxorubicin from its liposomal formulation, Doxil, for 24 h. This work demonstrates the chemical compatibility of amphiphilic, orthogonally self-assembled systems and the range of their drug-delivering capabilities.

Synthetic molecular motor activates drug delivery from polymersomes.

The design of stimuli-responsive systems in nanomedicine arises from the challenges associated with the unsolved needs of current molecular drug delivery. Here, we present a delivery system with high spatiotemporal control and tunable release profiles. The design is based on the combination of an hydrophobic synthetic molecular rotary motor and a PDMS-b-PMOXA diblock copolymer to create a responsive self-assembled system. The successful incorporation and selective activation by low-power visible light (λ = 430 nm, 6.9 mW) allowed to trigger the delivery of a fluorescent dye with high efficiencies (up to 75%). Moreover, we proved the ability to turn on and off the responsive behavior on demand over sequential cycles. Low concentrations of photoresponsive units (down to 1 mol% of molecular motor) are shown to effectively promote release. Our system was also tested under relevant physiological conditions using a lung cancer cell line and the encapsulation of an Food and Drug Administration (FDA)-approved drug. Similar levels of cell viability are observed compared to the free given drug showing the potential of our platform to deliver functional drugs on request with high efficiency. This work provides an important step for the application of synthetic molecular machines in the next generation of smart delivery systems.

D55. A Tunable Nanoparticle-based Botulinum Toxin Formulation for Extended Duration of Therapeutic Effect

PURPOSE: Botulinum toxins (BoNT) are increasingly popular neuromodulators with an array of aesthetic and neurological indications. However, these agents are limited by their duration of effect, necessitating frequent redosing. We aim to develop a nanoparticle-based delivery system to extend BoNT release and characterize its release profile. METHODS: Botulinum toxin A (BoNTa) neuromodulators were encapsulated within polymeric nanoparticles (NPs) using a kinetically controlled microfluidic assembly method. Dynamic light scattering was used to measure particle size and uniformity. ELISA was used to quantify the protein release profile. RESULTS: Particle sizes were uniform with most particles centered at 100nm and nearly all particles between 50-200nm. A tunable release profile was achieved, in which BoNTa could be released linearly or with an initial bolus followed by sustained release at the desired rate. Reproducibility of NP performance was demonstrated in 3 independent trials. Our early in-vivo and mechanistic studies have demonstrated preservation of toxin bioactivity and extended therapeutic effect in a rat model. CONCLUSION: We developed a novel nanoparticle-based Botox formulation capable of providing long-acting release of neuromodulator with tunable kinetics at designated dosage. This sustained release delivery modality enables superior therapeutic outcomes with less frequent re-dosing.

Fibro-Gel: An All-Aqueous Hydrogel Consisting of Microfibers with Tunable Release Profile and its Application in Wound Healing.

Injectable hydrogels are valuable tools in tissue engineering and regenerative medicine due to their unique advantages of injectability with minimal invasiveness and usability for irregularly shaped sites. However, it remains challenging to achieve scalable manufacturing together with matching physicochemical properties and on-demand drug release for a high level of control over biophysical and biomedical cues to direct endogenous cells. Here, the use of an injectable fibro-gel is demonstrated, a water-filled network of entangled hydrogel microfibers, whose physicochemical properties and drug release profiles can be tailored to overcome these shortcomings. This fibro-gel exhibits favorable in vitro biocompatibility and the capability to aid vascularization. The potential use of the fibro-gel for advancing tissue regeneration is explored with a mice excision skin model. Preliminary in vivo tests indicate that the fibro-gel promotes wound healing and new healthy tissue regeneration at a faster rate than a commercial gel. Moreover, it is demonstrated that the release of distinct drugs at different rates can further accelerate wound healing with higher efficiency, by using a two-layer fibro-gel model. The combination of injectability and tailorable properties of this fibro-gel offers a promising approach in biomedical fields such as therapeutic delivery, medical dressings, and 3D tissue scaffolds for tissue engineering.

3D bioprinting of gene delivery scaffolds with controlled release

Localized gene delivery via engineered scaffolds offers spatiotemporal control of the gene vector release. Here, we explored the capability of digital light processing based bioprinting to fabricate 3D scaffolds in hydrogels for controlled gene delivery. We demonstrated the compatibility of the method with three representative hydrogel biomaterials for gene delivery. We further investigated the highly tunable release profile with these scaffolds by creating and combining distinct release mechanisms of diffusion and ion exchange. The efficacy of gene delivery of these scaffolds was validated in vitro using 293T cells. Results from this work could potentially facilitate the development of synergistic and personalized gene therapies.

3D printed multi-growth factor delivery patches fabricated using dual-crosslinked decellularized extracellular matrix-based hybrid inks to promote cerebral angiogenesis.

Generally, brain angiogenesis is a tightly regulated process, which scarcely occurred in the absence of specific pathological conditions. Delivery of exogenous angiogenic factors enables the induction of desired angiogenesis by stimulating neovasculature formation. However, effective strategies of mimicking the angiogenesis process with exogenous factors have not yet been fully explored. Herein, we develop a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs), using extracellular matrix-based hybrid inks. We introduce a new hybrid biomaterial-based ink for printing patches through dual crosslinking mechanisms: Chemical crosslinking with aza-Michael addition reaction with combining methacrylated hyaluronic acid (HAMA) and vascular-tissue-derived decellularized extracellular matrix (VdECM), and thermal crosslinking of VdECM. 3D printing technology, a useful approach with fabrication versatility with customizable systems and multiple biomaterials, is adopted to print three-layered hydrogel patch with spatially separated dual GFs as outer- and inner-layers that provide tunable release profiles of multiple GFs and fabrication versatility. Consequently, these layers of the patch spatiotemporally separated with dual GFs induce excellent neovascularization in the brain area, monitored by label-free photoacoustic microscopy in vivo. The developed multi-GFs releasing patch may offer a promising therapeutic approach of spatiotemporal drugs releasing such as cerebral ischemia, ischemic heart diseases, diabetes, and even use as vaccines. STATEMENT OF SIGNIFICANCE: Effective strategies of mimicking the angiogenesis process with exogenous factors have not yet been fully explored. In this study, we develop a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs) using extracellular matrix-based hybrid inks. We introduce a new hybrid biomaterial-based ink through dual crosslinking mechanisms: Chemical crosslinking with aza-Michael addition, and thermal crosslinking. 3D printing technology is adopted to print three-layered hydrogel patch with spatially separated dual GFs as outer- and inner-layers that provide tunable release profiles of multiple GFs and fabrication versatility. Consequently, these layers of the patch spatiotemporally separated with dual GFs induce excellent neovascularization in the brain area, monitored by photoacoustic microscopy in vivo.

Amoxicillin-loaded multilayer pullulan-based nanofibers maintain long-term antibacterial properties with tunable release profile for topical skin delivery applications

Unique physiochemical and biological properties of nanofibers along with the choice of a wide variety of materials for both fabrication and tunable release patterns make nanofibers an ideal option for drug delivery. Loading antibacterial agents into nanofibers has attracted great deal of attention. Whilst there are several studies focusing on applying new generations of antibacterial materials, antibiotics are still the gold standard in clinical applications. Therefore, we aimed at introducing antibiotic-loaded nanofiber substrates with potential for topical skin delivery applications, reduced consumption of antibiotics and increased storage time. We applied Amoxicillin (AMX) as a model drug with low solubility and detected the presence of AMX in our nanofibers using FTIR and Raman spectroscopy. AMX-loaded Pullulan (Pull) nanofibers proved to maintain the antibacterial properties of the AMX drug after electrospinning, and to preserve the antibacterial properties for at least 8 months storage. The release trend can be tuned from burst release in mono-layer AMX:Pull nanofibers to sustained release if sandwiching the Pull layer between two hydrophobic electrospun layers (e.g. PLGA biopolymer). The AMX-loaded Pull construct can be considered as a novel nanofibrous solid dispersion of a poorly water-soluble drug for efficient topical application of antibiotics in wound healing and skin treatments.

Microgels Formed by Spontaneous Click Chemistries Utilizing Microfluidic Flow Focusing for Cargo Release in Response to Endogenous or Exogenous Stimuli.

Protein therapeutics have become increasingly popular for the treatment of a variety of diseases owing to their specificity to targets of interest. However, challenges associated with them have limited their use for a range of ailments, including the limited options available for local controlled delivery. To address this challenge, degradable hydrogel microparticles, or microgels, loaded with model biocargoes were created with tunable release profiles or triggered burst release using chemistries responsive to endogenous or exogeneous stimuli, respectively. Specifically, microfluidic flow-focusing was utilized to form homogenous microgels with different spontaneous click chemistries that afforded degradation either in response to redox environments for sustained cargo release or light for on-demand cargo release. The resulting microgels were an appropriate size to remain localized within tissues upon injection and were easily passed through a needle relevant for injection, providing means for localized delivery. Release of a model biopolymer was observed over the course of several weeks for redox-responsive formulations or triggered for immediate release from the light-responsive formulation. Overall, we demonstrate the ability of microgels to be formulated with different materials chemistries to achieve various therapeutic release modalities, providing new tools for creation of more complex protein release profiles to improve therapeutic regimens.

Fused deposition modeling three-dimensional printing of flexible polyurethane intravaginal rings with controlled tunable release profiles for multiple active drugs

We designed and engineered novel intravaginal ring (IVR) medical devices via fused deposition modeling (FDM) three-dimensional (3D) printing for controlled delivery of hydroxychloroquine, IgG, gp120 fragment (encompassing the CD4 binding site), and coumarin 6 PLGA-PEG nanoparticles (C6NP). The hydrophilic polyurethanes were utilized to 3D-print reservoir-type IVRs containing a tunable release controlling membrane (RCM) with varying thickness and adaptable micro porous structures (by altering the printing patterns and interior fill densities) for controlled sustained drug delivery over 14 days. FDM 3D printing of IVRs were optimized and implemented using a lab-developed Cartesian 3D printer. The structures were investigated by scanning electron microscopy (SEM) imaging and in vitro release was performed using 5 mL of daily-replenished vaginal fluid simulant (pH 4.2). The release kinetics of the IVR segments were tunable with various RCM (outer diameter to inner diameter ratio ranging from 1.12 to 2.61) produced from FDM 3D printing by controlling the printing perimeter to provide daily zero-order release of HCQ ranging from 23.54 ± 3.54 to 261.09 ± 32.49 µg/mL/day. IgG, gp120 fragment, and C6NP release rates demonstrated pattern and in-fill density-dependent characteristics. The current study demonstrated the utility of FDM 3D printing to rapidly fabricate complex micro-structures for tunable and sustained delivery of a variety of compounds including HCQ, IgG, gp120 fragment, and C6NP from IVRs in a controlled manner.Graphical abstract

PEGylated Oligothioetheramide Prodrugs Activated by Host Serum Proteases.

Due to the increasing prominence of antibiotic resistance, novel drug discovery and delivery approaches targeting bacteria are essential. In this work we evaluate a prodrug design to improve the cytotoxic profile of polycationic oligothioetheramides (oligoTEAs), which are promising antimicrobials. Herein we chemically modify the oligoTEA, PDT-4G, with a polyethylene glycol (PEG) and show that 1, 2, and 5 kDa PEGs mitigate cytotoxicity. As PEGylation reduces antibacterial activity, we evaluate two peptide linkers which, unlike oligoTEAs, are susceptible to proteolytic cleavage in serum. To gain insight into the prodrug reactivation, two linkers were tested, the 5-residue peptide sequence LMPTG, and the dipeptide sequence VC-PABC. In the presence of 20 % serum, prodrugs made with the VC-PABC linker successfully inhibited bacterial growth. Overall, we observed reactivation of oligoTEAs facilitated by serum protease cleavage of the peptide linkers. This work opens the door to the future design of antimicrobial prodrugs with tunable release profiles.

Controllable multi-phase protein release from in-situ hydrolyzable hydrogel

Using hydrogels to control the long-term release of protein remains challenging, especially for in-situ forming formulations. The uncontrollable burst release in the initial phase, the halted release in the subsequent phase, and the undesired drug dumping at the late stage are some obstacles hydrogel-based depots commonly encounter. In this study, we report hydrolyzable dextran-based hydrogels crosslinked by Michael addition to demonstrate a systematic solution to solve these problems. First, the polymer concentration was used as the critical parameter to control the proportion of releasable versus physically trapped protein molecules in the initial hydrogel meshwork. Subsequently, the dynamic change of the hydrogel meshwork was modulated by the crosslinking density and the cleavage rate of ester linkers. To this end, we designed and synthesized a series of ester linkers with hydrolytic half-life ranging from 4 h to 4 months and incorporate them into the hydrogel. Controlled release was demonstrated for model proteins varied in size, including lysozyme (14 kDa), bovine serum albumin (66 kDa), immunoglobulin G (150 kDa), and bevacizumab (149 kDa). In particular, sustained release of IgG ranging from 10 days to 8 months was achieved. Lastly, a tunable multi-phase release profile was made feasible by incorporating multiple ester linkers into one hydrogel formulation. The linker's half-life determined each phase's release duration, and the linkers' mixing ratio determined the corresponding release fraction. The reported hydrogel design engenders a versatile platform to address the needs for long-term and readily adjustable protein release for biomedical applications.

On-demand and tunable dual wavelength release of antibody using light-responsive hydrogels.

There has been an increased interest in the use of protein therapeutics, especially antibodies, for the treatment of a variety of diseases due to their high specificity to tissues and biological pathways of interest. However, the use of antibodies can be hindered by physical aggregation, degradation, and diffusion when injected in vivo leading to the need for antibody-releasing depots for the controlled and localized delivery within tissues of interest. Here, we investigated photolabile hydrogel chemistries for creating on-demand and tunable antibody release profiles. Innovative, scalable synthetic procedures were established and applied for fabricating hydrogels with nitrobenzyl (NB) and coumarin (CMR) photolabile crosslinks that responded to clinically relevant doses of long-wavelength UV and short-wavelength visible light. This synthetic procedure includes a route to make a CMR linker possessing two functional handles at the same ring position with water-stable bonds. The photocleavage properties of NB and CMR crosslinked hydrogels were characterized, as well as their potential for translational studies by degradation through pig skin, a good human skin mimic. The mechanism of hydrogel degradation, bulk versus surface eroding, was determined to be dependent on the wavelength of light utilized and the molar absorptivity of the different photolabile linkers, providing a facile means for altering protein release upon hydrogel degradation. Further, the encapsulation and on-demand release of a model monoclonal antibody was demonstrated, highlighting the ability to control antibody release from these hydrogels through the application of light while retaining its bioactivity. In particular, the newly designed CMR hydrogels undergo surface erosion-based protein release using visible light, which is more commonly used clinically. Overall, this work establishes scalable syntheses and relevant pairings of formulation-irradiation conditions for designing on-demand and light-responsive material systems that provide controlled, tunable release of bioactive proteins toward addressing barriers to preclinical translation of light-based materials and ultimately improving therapeutic regimens.

Scalable microfabrication of drug-loaded core–shell tablets from a single erodible polymer with adjustable release profiles

Oral tablets with tunable release profiles have emerged to enhance the effectiveness of therapies in different clinical conditions. Although the concept of tablets with adjustable release profiles has been studied before, the lack of a fast and scalable production technique has limited their widespread application. In this study, a scalable fabrication method was developed to manufacture controlled-release polyanhydride tablets. A new polymeric core–shell tablet design is also proposed, that in conjunction with a micro-fabrication procedure, allows for achieving tunable release profiles required in personalized medicine in small-size tablets. Utilizing a surface-erodible polymeric carrier in the fabrication of the new tablet design resulted in achieving adjustable release profiles and improvements in the drug-loading capacity of the delivery system which allows for delivering a flexible amount of therapeutics with desirable patterns to patients. The proposed fabrication techniques allow for scalable production of personalized tablets with the high resolution required in precision medicine and hence have a high potential for clinical translation.

Evaluation of amorphous dispersion of a cellulose ester-colophony mix for ibuprofen controlled release processed by HME and spin coating

Recently, there has been a rapid growth of using bio-based materials in pharmaceutical applications, due to their low cost and availability. In this study, natural composition of cellaburate (cellulose-ester) and colophony (pine-resin) was used to prepare films to control ibuprofen release from its amorphous solid dispersion. The effect of two preparation technologies of spin-coating and hot-melt-extrusion was studied on the physicochemical properties and in vitro dissolution/release behavior. Physical stability was evaluated for 12 w at 54 %RH/22 °C. Characterization involved using PLM/DSC/MTDSC/ATRFTIR/TGA/SEM and PXRD. Ibuprofen was amorphously-dispersed at 30 %(w/w) in 35:65 colophony:cellaburate films. Spin-films were more physically stable over 12 w; however, controlled release of ibuprofen was achieved mainly from hot-melt-extruded-films for 5 h. Both films have shown first-order release kinetics; whereby polymeric swelling and relaxation likely governed the release. The successful preparation of cellaburate-colophony platform that has achieved tunable release profiles of poorly water-soluble drug holds the potential for further drug delivery development.

Prolonged melittin release from polyelectrolyte-based nanocomplexes decreases acute toxicity and improves blood glycemic control in a mouse model of type II diabetes

Gating modifier toxins (GMTs) from animal venom have shown great potential in controlling blood glucose levels in type II diabetes (T2D), but their high acute toxicity and quick clearance in the body hamper their potential therapeutic use. Inspired by their highly positive charge, we have developed a nanocomplex system based on polyelectrolytes, in which strong interactions form between positively charged GMTs and negatively charged dextran sulfate (DS). Using melittin as a model GMT and adapting flash nanocomplexation (FNC) technology for complex preparation, uniform nanocomplexes (polydispersity index: ~0.1) with high melittin encapsulation efficiency (~100%), high payload capacity (~30%), and tunable release profiles were formulated. In contrast to the high acute liver toxicity and low survival rate (60% after 8days) observed after a single intraperitoneal (i.p.) injection of 3mg/kg free melittin, melittin-loaded nanocomplexes displayed improved safety (100% survival after 8days) due to prolonged melittin release. In a mouse model of T2D, a single i.p. injection of nanocomplexes decreased the blood glucose level to 12mmol/L within 12h and maintained it within the therapeutic range (<15mmol/L) for 48h. In addition, body weight decreased following treatment. This GMT/DS binary system shows great promise due to its simple components, facile preparation method, and enhanced potential druggability, including a decreased dosing frequency, decreased acute toxicity, and improved pathological indicators.

Synthesis of Cyclic Sulfite Diesters and their Evaluation as Sulfur Dioxide (SO2) Donors

Although sulfur dioxide (SO2 ) finds widespread use in the food industry as its hydrated sulfite form, a number of aspects of SO2 biology remain to be completely understood. Of the tools available for intracellular enhancement of SO2 levels, most suffer from poor cell permeability and a lack of control over SO2 release. We report 1,2-cyclic sulfite diesters as a new class of reliable SO2 donors that dissociate in buffer through nucleophilic displacement to produce SO2 with tunable release profiles. We provide data in support of the suitability of these SO2 donors to enhance intracellular SO2 levels more efficiently than sodium bisulfite, the most commonly used SO2 donor for cellular studies.