Month: February 2019

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. )