Orthoformate Research Articles

A new insight into the mechanism of loading of Granisetron, Naltrexone and Risperidone in poly(ortho ester) and poly (lactic-co-glycolic acid) as the controlled release drug delivery systems using a computational molecular approach

Owing to the good biocompatibility, bioavailability, biodegradability, and low toxicity of polymeric nanoparticles, considerable research interest has been generated. These polymeric carriers enhance the therapeutic index and improve controlled drug release. In this study, molecular dynamics (MD) simulation of six designed systems were conducted to compare poly(ortho ester) (POE) and poly (lactic-co-glycolic acid) (PLGA) polymeric nanoparticles as carriers and delivery systems for three drugs: Granisetron, Naltrexone, and Risperidone. These drugs are FDA-approved under the brand name SUSTOL (Granisetron for anti-nausea and vomiting post-heavy chemotherapy), VIVITROL (Naltrexone for managing alcohol or opioid use disorder), and RISPERDAL CONSTA (Risperidone for treating schizophrenia). Various parameters, such as interaction energy, radius of gyration (Rg), solvent accessible surface area (SASA), distance, hydrogen bond, radial distribution function (RDF), and root mean square fluctuation (RMSF), were investigated. The MD simulations show good consistency with FDA-approved data, clearly illustrate why PLGA is suitable for NAL and RIS, and POE for GRS, as carriers in drug delivery. The findings, detailing mechanisms of polymer-drug interactions, have potential applications in (i) manufacturing and production of novel sustained-release drugs and biopolymers, (ii) identifying suitable patterns, and (iii) rationally designing new controlled-release drugs based on future artificial intelligence methods.

Protonated acetylene in the z = 0.89 molecular absorber toward PKS 1830-211

We report the first interstellar identification of protonated acetylene, C2H3+, a fundamental hydrocarbon, in the z = 0.89 molecular absorber toward the gravitationally lensed quasar PKS 1830–211. The molecular species is identified from clear absorption features corresponding to the 212–101 (rest frequency 494.034 GHz) and 111–000 (431.316 GHz) ground-state transitions of ortho and para forms of C2H3+, respectively, in ALMA spectra toward the southwestern image of PKS 1830-211, where numerous molecules, including other hydrocarbons, have already been detected. From the simple assumption of local thermodynamic equilibrium (LTE) with cosmic microwave background photons and an ortho-to-para ratio of three, we estimate a total C2H3+ column density of 2 × 1012 cm−2 and an abundance of 10−10 compared to H2. However, formation pumping could affect the population of metastable states, yielding a C2H3+ column density higher than the LTE value by a factor of a few. We explore possible routes to the formation of C2H3+, mainly connected to acetylene and methane, and find that the methane route is more likely in PDR environment. As one of the initial hydrocarbon building blocks, C2H3+ is thought to play an important role in astrochemistry, in particular in the formation of more complex organic molecules.

Enhanced thermoelectric performances in graphene nanoribbons via BN dimers doping: Theoretical study

Improving the thermoelectric performance of designed graphene nanoribbons is a key stage in the production of thermoelectric nanodevices with many applications. The chemical doping allows armchair graphene nanoribbons (AGNRs) to exhibit controllable thermoelectric characteristics. Here, we use density functional theory-based tight-binding (DFTB) coupled with the non-equilibrium Green's function (NEGF) to study the electronic and thermoelectric properties of AGNR with boron nitride (BN) dimers at room temperature. Changing the concentrations (from 4.17 % (BN)1-structure to 12.5 % (BN)3-structure) and geometrical pattern (ortho, meta, and para form) of BN dimers in the graphene nanoribbons may have a significant effect on the thermoelectric (TE) properties. Our results show that the TE properties of AGNR depend not only on the amount of BN dimers but also on the arrangement of the BN dimers in the AGNR. The thermoelectric figure of merit (ZT) of nanoribbons at room temperature has improved from less than 0.7 to more than 2. These results could be used as an indicator to design nanodevices that have good TE applications.

Lutein-Based pH and Photo Dual-Responsive Novel Liposomes Coated with Ce6 and PTX for Tumor Therapy.

Liposomes are considered the best nanocarrier for delivering cancer drugs such as chlorin e6 (Ce6) and paclitaxel (PTX). However, the poor stability and non-selectivity release of liposomes may severely limit their further applications. In this study, based on the characteristics of lutein (L) photo-response and orthoester (OE) acid-response, stable and dual-responsive liposomes (Dr-lips) have been prepared. The Dr-lips exhibited a spherical shape with a uniform size of approximately 58.27 nm. Moreover, they displayed a zeta potential ranging from -45.45 to -28.25 mV and showed excellent storage stability, indicating stable colloidal properties. Additionally, they achieved high drug encapsulation rates, with 92.27% for PTX and 90.34% for Ce6, respectively. Meanwhile, under near-infrared (NIR) light at 660 nm, Ce6 plays a key role in accelerating the photodegradation rate of lutein and PEG-OE-L while also enhancing tissue penetration ability. Additionally, Dr-lips loaded with Ce6 and PTX not only displayed excellent pH and photo dual-responsiveness for targeted delivering and releasing but also showed remarkable reactive oxygen species (ROS) generation capacity and impressive anti-tumor activity in vitro. Therefore, it provides a novel strategy for optimizing stability and enhancing their targeted drug delivery of liposome.

PH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

PH-Sensitive Cationic Polymer/DNA Nano-assemblies for Efficient Gene Transfection in Neuroma Cells

Transfection of functional genetic molecules into neuroma cells to efficiently manipulate gene expression is of great significance in neuro-associated gene therapy. However, most of the current neuroma cell gene carriers are based on viruses, which often suffer from inherent immunogenicity, carcinogenicity, and insertional mutagenesis. Here, a pH-sensitive linear poly(ortho ester) polycation (POP) with a uniform distribution of tertiary amine and hydroxyl groups is prepared by ring-opening polymerization between 4,4′-(oxybis(methylene))bis(2-methoxy-1,3-dioxolane) (OEDe) and piperazine. The prepared POP/DNA nano-assemblies show good stability and ultrasensitively controlled DNA release. Significantly, this linear polymer exhibits good biocompatibility and highly specified transfection efficiency (∼80%) on human neuroblastoma cells (SH-SY5Y), which is also serum-tolerant and exhibits deeper transfection depth. Besides, the non-responsive poly(ethylene glycol) diglycidyl ether (EGDE) polycation (PEP) is set as a control, fully demonstrating that the gene carrier POP has great potential in neuroma therapy.

Dynamic crosslinked polymeric nano-prodrugs for highly selective synergistic chemotherapy

To achieve highly selective synergistic chemotherapy attractive for clinical translation, the precise polymeric nano-prodrugs (PPD-NPs) were successfully constructed via the facile crosslinking reaction between pH-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug (Pt(IV)-1). PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin (DMC). Moreover, PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure, suitable negative potentials and low critical micelle concentration (CMC), improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular pH, promoted efficient disintegration and drug release at tumoural intracellular pH/glutathione, and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2, achieving significant tumour suppression while decreasing the side effects. Thus, the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy.

Hydrogenolysis of Carboxylic Ortho Esters.

It is demonstrated for the first time that carboxylic ortho esters may be reduced to acetals using hydrogen as the reducing agent. Hydrogenolysis was performed under mild conditions over commercially available hydrogenation catalysts (5% Pd/C and 5% Pt/C). The present method is especially useful for the selective transformation of carboxylic acids and lactones into acetals.

Heck Reaction of 2-Oxyacrylates with Aryl Bromides: A Common Route to Monoaryl Pyruvates and Ortho Ester-Protected Monoaryl Pyruvates.

A palladium-catalyzed Heck reaction between 2-oxyacrylates and aryl bromides was developed, where DavePhos was a unique ligand that efficiently promoted the reaction. The products, 2-oxycinnamates, served as excellent precursors, providing synthetically useful monoaryl pyruvates or ortho ester-protected monoaryl pyruvates depending on the nature of the 2-oxy group. The formation of such ortho esters via alkoxide addition is novel, and computational studies identified a plausible mechanism with an oxyallyl zwitterion as the key intermediate.

Photoactive polymers-decorated Cu-Al layered double hydroxide hexagonal architectures: A potential non-viral vector for photothermal therapy and co-delivery of DOX/pCRISPR

Gene and drug co-delivery is considered a promising strategy in combination cancer therapy. In this study, we fabricated Cu-Al layered double hydroxide (LDH) decorated with nanoscale ortho-, meta-, and para-poly(phenylenediamine), and afterward, doxorubicin (DOX) was loaded into nanoparticles. Finally, LDH was wrapped with plasmid CRISPR (pCRISPR). The modified nanohexagonals had particle sizes of approximately less than 100 nm with drug uptake up to 62.3%. pH-responsive nanocarriers exhibited higher cargo release in an acidic environment (pH 5.5) compared to a neutral buffer of pH 7.4. CLSM analysis demonstrated internalization in MEF-7 and HEK-293 cells with high transfection efficiency, further confirming them as promising nanostructures in cargo delivery. Besides, the potential usage of the cell-imprinted technique in order to increase the interactions to the cells, and enhance the cellular internalizations/transfections were assessed and showed a considerable increase (up to 72%) in the cellular internalizations. LDH nanostructures displayed high biocompatibility against HEK-293 and PC12 cells after 24 and 48 h. While they had no significant impact on the viability of MCF-7 cells with the assistance of the cell-imprinted method, these non-viral vectors significantly reduced the viability of HT-29 cells, showing their anti-cancer activity. Ortho, meta, and para forms of the poly(phenylenediamine)s decorated on the surface of the LDH showed transfection efficiencies up to 29.1, 28.2, and 40.1%, respectively. Therefore, this study could be considered the highest record of the pCRISPR delivery using a composite substrate in the literature.

Acid-sensitive polymeric prodrug micelles for achieving enhanced chemo-photodynamic therapy

Multimodal combination therapy is considered more effective in cancer treatment than monotherapy, because it overcomes some limitations of monotherapy. In this study, acid-sensitive polymeric prodrugs consisting of photosensitizer (Hemin) and ortho ester-terminated PEG were synthesized and loaded with doxorubicin (DOX) to obtain a dual-modal therapeutic nanoplatform (Hemin/DOX-M). This nanoplatform demonstrated good drug encapsulation and stability. In vitro experiments have confirmed that Hemin/DOX-M can be effectively internalized by HepG2 cells, trigger rapid drug release via the cleavage of ortho ester and alleviate tumor hypoxia to amplify the PDT effect under laser irradiation. In vivo experiments revealed that Hemin/DOX-M caused decreased hemolysis and selective accumulation in the tumor tissue, thereby significantly reducing the side effects. Intriguingly, In vivo antitumor evaluation revealed that Hemin/DOX-M had stronger capability at tumor growth inhibition (TGI, 79.63%) than chemo- or photodynamic therapy alone. Overall, Hemin/DOX-M is a promising candidate to increase therapeutic efficacy by achieving combination therapy against tumors.

Synthesis of amykitanose, an O-carbamoyl sugar component of the antibiotic amycolamicin

The first synthesis of amykitanose, an O-carbamoyl pyranose component of the potent broad-spectrum antibiotic amycolamicin, has been accomplished from l-fucose in eight steps. The key transformations involve a stereochemical inversion at the C2 asymmetric center of an l-fucose derivative via an oxidation/reduction sequence, a regioselective installation of the 3-acetoxy functionality by acid-promoted hydrolysis of a cyclic orthoester, and a titanium tetrabromide-mediated hydrolysis of a penultimate glycoside intermediate.

Fluoride‐Ortho Ester Dimer‐Based pH‐Sensitive Nanoparticles for Oxygen Delivery and Enhanced Photodynamic Therapy

AbstractHypoxia is one of the major factors that affect the efficiency of photodynamic therapy (PDT). However, the strategy of using nano‐oxygen carriers to reverse tumor hypoxia still has some drawbacks, which limit its clinical application and translation. Herein, it is reported a method for preparing pH‐sensitive nano‐oxygen carrier for reversing tumor hypoxia and enhancing the efficiency of PDT. Briefly, perfluorocarbons (PFC) with different chain‐lengths (7F or 15F) are linked by acid‐labile ortho ester bonds, then further self‐assembled with Chlorin e6 to form two pH‐sensitive nanodrugs. In vitro tests demonstrate that these nanodrugs possessed good physicochemical properties, including high stability, anti‐adsorption capability, and high oxygen‐loading capacity (24.5 mg L−1). In vivo studies reveal that this system can remarkably alleviate tumor hypoxia and inhibit tumor growth, and 15F@OE dimer particles display the highest antitumor efficiency (84.2%). Overall, this study presents a simple and efficient strategy to deliver oxygen and drugs to tumor tissue, thereby overcoming the limitation of hypoxia‐mediated PDT in cancer treatment.

Shifting Target Reaction from Oxygen Reduction to Superoxide Disproportionation by Tuning Isomeric Configuration of Quinone Derivative as Redox Mediator for Lithium-Oxygen Batteries.

Quinones having a fully conjugated cyclic dione structure have been used as redox mediators in electrochemistry. 2,5-Ditert-butyl-1,4-benzoquinone (DBBQ or DB-p-BQ) as a para-quinone derivative is one of the representative discharge redox mediators for facilitating the oxygen reduction reaction (ORR) kinetics in lithium-oxygen batteries (LOBs). Herein, we presented that the redox activity of DB-p-BQ for electron mediation was possibly used for facilitating superoxide disproportionation reaction (SODR) by tuning the isomeric configuration of the carbonyl groups of the substituted quinone to change its reduction potentials. First, we expected a molecule having its reduction potential between oxygen/superoxide at 2.75 V versus Li/Li+ and superoxide/peroxide at 3.17 V to play a role of the SODR catalyst by transferring an electron from one superoxide (O2-) to another superoxide to generate dioxygen (O2) and peroxide (O22-). By changing the isomeric configuration from para (DB-p-BQ) to ortho (DB-o-BQ), the reduction potential of the first electron transfer (Q/Q-) of the ditert-butyl benzoquinone shifted positively to the potential range of the SODR catalyst. The electrocatalytic SODR-promoting functionality of DB-o-BQ kept the reactive superoxide concentration below a harmful level to suppress superoxide-triggered side reaction, improving the cycling durability of LOBs, which was not achieved by the para form. The second electron transfer process (Q-/ Q2-) of the DB-o-BQ, even if the same process of the para form was not used for facilitating ORR, played a role of mediating electrons between electrode and oxygen like the Q/Q- process of the para form. The ORR-promoting functionality of the ortho form increased the LOB discharge capacity and reduced the ORR overpotential.

Effective synthesis of dialkyl carbonate from CO2 and alcohols using dibutyltin(IV) oxide catalyst and dehydrating agents

The combination of a dibutyltin(IV) oxide catalyst with an ortho ester as the dehydrating agent exhibited high activity for the direct synthesis of diethyl carbonate from CO2 and ethanol in 78% yield. With water as a by-product limiting the reaction, a recoverable dehydrating agent is required. When alkoxysilanes were employed for this purpose, various dialkyl carbonates were obtained in yields of 33–45%.

General and Efficient Synthesis of Quinazolinones under CF3COOH Catalysis and Solvent‐Free Conditions

AbstractWe herein reported the general and facile synthesis of diffferently substituted quinazolinones by using ortho ester as C1 synthon and CF3COOH as the catalyst under solvent‐free conditions. That represents one of the most mild, practical and user‐friendly methodologies with easy‐separation procedure.

Cisplatin-Cross-Linked and Oxygen-Resupply Hyaluronic Acid-Based Nanocarriers for Chemo-photodynamic Therapy

Tumor microenvironment (TME) is known to play a critical role in cancer progression and contributes to treatment failure or success. Herein, a versatile nanoplatform [HAFOE-Ce6/Pt-NPs(O2)] with cisplatin (Pt) cross-linking, chlorin e6 (Ce6) loading, pH sensitivity, active targeting, and oxygen resupply was developed to address this problem. This nanosystem presents as a spherical shape with a small size of 175.4 ± 2.16 nm and a negative charge of −25.32 ± 3.04 mV. Hyaluronic acid (HA) as the starting material not only improved the biocompatibility of the nanosystem but also enhanced cellular uptake by targeting the CD44 receptor. Interestingly, cisplatin could serve as both a cross-linker and anticarcinogen to increase the blood stability and therapeutic performance. Additionally, the micelles disintegration and drug release could be accelerated by the cleavage of ortho ester at low pH. More importantly, the fluorocarbon inside the particles has the ability to load oxygen and in situ release oxygen at tumor regions, which greatly reduced tumor hypoxia. In vitro and in vivo results demonstrated that HAFOE-Ce6/Pt-NPs(O2) could efficiently inhibit tumor growth by combined chemo-photodynamic therapy under 660 nm laser irradiation by way of oxygen sensitization, leading to a high mice survival rate (83.33%). Overall, this combined nanosystem could take advantage of TME while overcoming its disadvantages and was an efficient nanoplaform for cancer treatment.

PH-sensitive and tumor-targeting nanogels based on ortho ester-modified PEG for improving the in vivo anti-tumor efficiency of doxorubicin

In this study, we aim to develop the pH-sensitive and tumor-targeting nanogels based on the co-polymerization of three terminal allyl-functionalized components, including ortho ester-conjugated mPEG (mPEG-MOE), ortho ester crosslinker (OEAM) and phenylboronic acid (APBA). The hybrid nanogels displayed a typical spherical structure with a diameter around 200 nm observed by dynamic light scattering (DLS) and scanning electron microscopy (SEM). The prepared nanogels possessed a good stability in neutral conditions, while displayed pH-triggered drug release profiles. Furthermore, in vitro study of cellular uptake and cytotoxicity indicated that the nanogels possessed the highest drug accumulation and cytotoxicity against EMT6 cells. In vivo antitumor examination suggested that these nanogels brought out excellent efficacy in enhancing drug concentration, restraining tumor growth, and prolonged the survival time of tumor-bearing mice. Thus, the prepared multi-functional nanogels possess great potentials for drug delivery in tumor treatment.

Activator-free reactions of carboxylic ortho esters with cyclic β-diketones

Activator-free reactions of carboxylic ortho esters with cyclic β-diketones

A sequentially responsive nanogel via Pt(IV) crosslinking for overcoming GSH-mediated platinum resistance

Chemotherapy efficiency of platinum(II) (Pt(II)) is often attenuated owing to the low intracellular drugs concentration and glutathione (GSH)-mediated detoxification. To address these problems, we fabricated a step-by-step responsive nanogel (~160 nm) by copolymerization between four functional monomers. Hydrophilic methoxypolyethylene glycols (mPEG) distributedrandomly on the surface of particles endowed the nanogel with “stealth” property in blood circulation, while the chemical crosslinking inside particles by platinum(IV) (Pt(IV)) linker remarkably increased the stability of nanogel in vivo. These advantages of nanogels leaded to higher accumulation at tumor region (6.4% ID/g), followed by triggering the dePEGylation effect by the cleavage of ortho ester at tumoral extracellular pH. Meanwhile, the exposed phenylboric acid (PBA) could significantly increase cellular uptake and intracellular drugs levels by targteing sialic acid residues on the cells membrane. More importantly, this nanogels could further deplete intracellular glutathione (GSH) by the dual-regulation of platinum(IV) and arylboronic ester, resulting in enhanced platinum(II) toxicity both in vitro and in vivo, eventually achieving superior inhibition rate (79.14%) in A549/DDP tumor. Thus, the sequentially responsive nanogel could be considered as an effective strategy for cancer treatment.