Author: novelconjugates

MMT, Npeoc-protected spermine, a valuable synthon for the solid phase synthesis of oligonucleotide oligospermine conjugates via guanidine linkers

Solid phase spermine oligomerization via guanidine linkers was achieved using activated thiourea coupling reaction with primary amino group. Disymmetric spermine synthon was efficiently synthesised in eight steps from spermine. MMT group was used as coupling monitor and resulting oligomeric spermines were conjugated to oligonucleotides. (Bioorganic & Medicinal Chemistry., Volume 19, Issue 6, 15 March 2011, Pages 1972-1977.)

Amphiphilic hyaluronic acid derivatives toward the design of micelles for the sustained delivery of hydrophobic drugs

The idea of this study was to combine hyaluronic acid (HA) viscosupplementation and a local/controlled delivery of a hydrophobic anti-inflammatory drug. To this aim, we investigated the ability of an octenyl succinic anhydride (OSA) modified HA (OSA-HA), to act as a solubility enhancer and as a platform for slow release of hydrophobic drug(s). This novel HA derivative could act as a viscosupplementation agent and, for this reason, a rheological study was conducted along with calorimetric analysis. Differential scanning calorimetry (DSC) results revealed that the ability of HA to sequester water is enhanced by the introduction of lipophilic functions within HA molecules, resulting in a decrease of the fraction of free water able to freeze compared to the unmodified HA. Moreover, OSA-HA solutions appear to be an appropriate tool to be used in viscosupplementation therapy owing to their suitable viscoelastic features. Our results indicate that OSA-HA is able to self-assemble into micelles, load a hydrophobic drug and release the active molecule with controlled kinetics. In particular, the analysis of release profiles showed that, in all cases, drug diffusion into the gel is faster compared to gel/drug dissolution, being the dissolution contribution more relevant as the OSA-HA concentration increases.(Carbohydr Polym. 2014 Feb 15;102:110-6)

Preparation and characterization of octenyl succinic anhydride modified agarose derivative

Agarose was successfully modified with octenyl succinic anhydride (OSA) and the factors affecting OSA modifying process were studied. The degree of substitution (DS) could be regulated from 0.02 to 0.21 by changing the reaction condition, simultaneously the molecular weight of the OSA-agarose (OSAG) varied from 342 kD to 483 kD. FT-IR spectrum of the OSAG at 1734 cm-1 and 1576 cm-1 revealed characteristic absorption peaks of the ester carbonyl groups (CO) and the carboxylate (RCOO-), respectively. NMR spectrum of the OSAG suggested the main substitution occurred at the C-2 in the d-galactopyranose. The SEM image of agarose showed the porous network structure became dense and the fiber became thin after OSA modification. Compared with original agarose, the prepared OSAG showed novel physical properties including low gelling and melting temperature and high transparency. The remaining gelation ability and newly introduced amphiphilic character anticipate potential application as functional polysaccharide materials in foods. (Food Chem. 2019 May 1;279:30-39.)

Superior anti-neoplastic activities of triacontanol-PEG conjugate: synthesis, characterization and biological evaluations

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Triacontanol (TA, C30H62O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis-inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-κB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti-malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25 ng·mL−1·h−1,p < .001), mean residence time (8.46 vs. 2.95 h, p < .001) and elimination half-life (7.78 vs. 2.57 h, p < .001) compared to those of original TA. Moreover, mPEG2K-SA-TA appeared to be safe in preliminary toxicological assessment. PEGylated TA also emerged as a functional carrier to deliver hydrophobic chemotherapeutic agents, since it readily self-assembled to micelles in aqueous solution with a low critical micelle concentration (CMC, 19.1 µg·mL−1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy.(Drug Deliv. 2018; 25(1): 1546–1559.)

Self-assembled nanoparticles based on chondroitin sulfate-deoxycholic acid conjugates for docetaxel delivery: Effect of degree of substitution of deoxycholic acid

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Hydrophobically-modified polymers based on chondroitin sulfate with different degree of substitution (DS) of deoxycholic acid (DOCA) were developed for docetaxel delivery. Chondroitin sulfate-deoxycholic acid (CSAD) bioconjugates were synthesized via the linker of adipic dihydrazide by amide bond. They were characterized with spherical shape, mean diameter of around 165.2 nm and negative zeta potential (⿿14.87 to ⿿20.53 mV). An increase of DOCA DS reduced size of nanoparticles, while increasing drug loading efficiency. Drug release in vitro showed a triphasic sustained pattern and higher accumulative drug release percentage was observed with increased DS of DOCA on polymer. Self-assemblies with higher DS also had enhanced internalization of nanoparticles and stronger cytotoxicity at the cellular level. The self-assemble nanoparticles demonstrate to be excellent targeting drug delivery systems and the desired therapeutics can be achieved via the alteration of DS.(Colloids and Surfaces B: Biointerfaces. Volume 146, 1 October 2016, Pages 235-244.)

Amphiphilic polysaccharides as building blocks for self-assembled nanosystems: molecular design and application in cancer and inflammatory diseases

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Polysaccharides (PSs) have been extensively studied in healthcare applications; here, we focus our attention on their use as components of nanomaterials in the management of cancer and inflammatory pathologies. Key advantages of PSs are easy availability, general biodegradability and biocompatibility, low or negligible toxicity, often a low immunogenicity and finally an ease of chemical modification. Here, we pay particular attention to the large family of amphiphilic PS derivatives (AMPDs); they are synthesized by modifying hydrophilic PSs with a variety of hydrophobic groups, which allow the constructs to self-assemble into various nanostructures in aqueous solution. This review focuses on AMPD-based self-assembled nanoparticles, from the chemical synthesis of AMPDs, through nanoparticle preparative strategies, to the most recent applications in cancer and inflammation management, including therapeutics, imaging and theranostics. We also offer an overview, which we feel lacks in the current literature, of the relation between the nature of the hydrophilic PSs and that of the hydrophobic components, of linkers, targeting groups and cross-linkers, and of the actual properties and in vivo fate of AMPD-based nanoparticles. Finally, we believe that this comprehensive insight into the possible effects of AMPDs’ structural components on the performance of nanosystems, can provide criteria for a rational and molecular level-based design of AMPDs. (Journal of Controlled Release. Volume 272, 28 February 2018, Pages 114-144.)

Effects of Chemical Conjugation of l-Leucine to Chitosan on Dispersibility and Controlled Release of Drug from a Nanoparticulate Dry Powder Inhaler Formulation

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This study investigated l-leucine-conjugated chitosan as a drug delivery vehicle in terms of dispersibility and controlled release from a nanoparticulate dry powder inhaler (DPI) formulation for pulmonary delivery using diltiazem hydrochloride (DH) as the model drug. DH-loaded nanoparticles of chitosan and conjugate were prepared by water-in-oil emulsification followed by glutaraldehyde cross-linking. Nanoparticles were characterized by dynamic light scattering for particle size, X-ray photoelectron spectroscopy for surface composition, and twin stage impinger for drug dispersibility. The controlled release of DH was studied in phosphate-buffered saline (pH 7.3 ± 0.2, 37 °C) using UV spectrophotometry. The fine particle fractions of conjugated chitosan with and without drug were higher than those of nonconjugated chitosan nanoparticles. The conjugate nanoparticles were superior to those of unmodified chitosan in drug loading, entrapment efficiency, and controlled release profile. The higher dispersibility was attributed to the amphiphilic environment of the l-leucine conjugate and hydrophobic cross-links, and the release profile reflects the greater swelling. The conjugated chitosan nanoparticles could be useful, after appropriate testing for biodegradability and toxicity, as an alternative carrier for lung drug delivery with enhanced aerosolization and prolonged drug release from nanoparticulate DPI formulations. (Mol Pharm. 2016 May 2;13(5):1455-66. )

Carnosine-LVFFARK-NH2 Conjugate: A Moderate Chelator but Potent Inhibitor of Cu2+-Mediated Amyloid β-Protein Aggregation

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Aggregation of amyloid-β (Aβ) protein stimulated by Cu2+ has been recognized as a crucial step in the neurodegenerative process of Alzheimer’s disease. Hence, it is of significance to develop bifunctional agents capable of inhibiting Aβ aggregation as well as Cu2+-mediated Aβ toxicity. Herein, a novel bifunctional nonapeptide, carnosine-LVFFARK-NH2 ( Car-LK7), was proposed by integrating native chelator carnosine ( Car) and an Aβ aggregation inhibitor, Ac-LVFFARK-NH2 (LK7). Results revealed the bifunctionality of Car-LK7, including remarkably enhanced inhibition capability on Aβ aggregation as compared to LK7 and a moderate Cu2+ chelating affinity ( KD = 28.2 ± 2.1 μM) in comparison to the binding affinity for Aβ40 ( KD = 1.02 ± 0.13 μM). The moderate Cu2+ affinity was insufficient for Car-LK7 to sequester Cu2+ from Aβ40-Cu2+ species, but it was sufficient to form ternary Aβ40-Cu2+- Car-LK7 complexes. Formation of the ternary complexes directed the aggregation into small, unstructured aggregates with little β-sheet structure. Car-LK7 also showed higher activity on arresting Aβ40-Cu2+-catalyzed reactive oxygen species production than Car. Cell viability assays confirmed the prominent protection activity of Car-LK7 against Cu2+-mediated Aβ40 cytotoxicity; Car-LK7 could almost eliminate Aβ40 cytotoxicity at an equimolar dose (cell viability increased from 59% to 99%). The research has thus provided new insight into the design of potent bifunctional agents against metal-mediated amyloid toxicity by conjugating moderate metal chelators and existing inhibitors. (ACS Chem Neurosci. 2018 Nov 21;9(11):2689-2700.)