Heparosan as a potential alternative to hyaluronic acid for the design of biopolymer-based nanovectors for anticancer therapy.

Glycosaminoglycans (GAGs) are important components of the extracellular matrix that have attracted great interest for drug delivery and pharmaceutical applications due to their diverse biological functions. Among GAGs, heparosan (Hep), a biosynthetic precursor of heparin, has recently emerged as a promising building block for the design of nanoparticles with stealth properties. Though this non-sulfated polysaccharide has a chemical structure very close to that of hyaluronic acid (HA), it distinguishes from HA in that it is biologically inert in the extracellular spaces in the body. In this study, we designed Hep- and HA-based nanogels (NGs) that differ only in the chemical nature of the hydrophilic shell. The nanogels were prepared in a very straightforward way from Hep and HA modified with a thermoresponsive copolymer properly designed to induce self-assembly below room temperature. This versatile synthetic approach also enabled further shell-crosslinking allowing an increase in the colloidal stability. After careful characterization of the un-crosslinked and crosslinked Hep and HA NGs in terms of size (Z-average diameters of un-crosslinked and crosslinked NGs ∼110 and 150 nm) and morphology, they were injected intravenously into tumor-bearing mice for biodistribution experiments. Interestingly, these show that the liver uptake of Hep nanogels is remarkably reduced and tumor accumulation significantly improved as compared to HA nanogels (intensity ratios of tumor-to-liver of 2.2 and 1.4 for the un-crosslinked and crosslinked Hep NGs versus 0.11 for the un-crosslinked and crosslinked HA ones). These results highlight the key role played by the shell-forming GAGs on the in vivo fate of nanogels, which correlates with the specific biological properties of Hep and HA.

Carvacrol activity & morphological changes in Mycobacterium tuberculosis.

AIM: Evaluating carvacrol, derivatives and carvacrol plus anti-TB (anti-tuberculous) drug combination activities in Mycobacterium tuberculosis as well as carvacrol cytotoxicity, efflux pump inhibitor activity and morphological changes in M. tuberculosis H37Rv. METHODS: Carvacrol (CAR) and derivatives' activities were determined by resazurin microtiter assay and drug interaction by resazurin drug combination microtiter. Carvacrol cytotoxicity in VERO cells and efflux pumps inhibitor activity by ethidium bromide assay were determined and scanning electron microscopy performed. RESULTS: Carvacrol MIC ranged from 19 to 156 µg/ml and carvacrol plus rifampicin combination showed synergistic effect in clinical isolates. No anti-M. tuberculosis activity improvement was observed with carvacrol derivatives. Carvacrol showed to be selective for M. tuberculosis, to have efflux pumps activity and to induce rough bacillary and agglomerates. CONCLUSION: Carvacrol shows good anti-M. tuberculosis activity and synergism with rifampicin.

Coumarin-containing thermoresponsive hyaluronic acid-based nanogels as delivery systems for anticancer chemotherapy.

Multi-stimuli responsive nanogels based on biocompatible hydrophilic polymers have emerged as promising drug delivery systems to improve anticancer therapy with hydrophobic drugs, through increase of circulating-time in the bloodstream, tumor-targeting and reduction of systemic toxicity. This paper reports on the synthesis, characterization and biological perspectives of light- and thermoresponsive hyaluronic acid (HA)-based nanogels containing coumarin as the photocleavable group. Newly synthesized nanogels exhibited interesting features: formation by a temperature-triggered self-assembly process, successful incorporation of poorly water-soluble molecules, light-responsiveness as demonstrated by a significant shift in the critical aggregation temperature after light irradiation, efficient internalization by cancer cells overexpressing the CD44 receptor of HA, ability to circulate for a prolonged period of time in the bloodstream after intravenous injection in mice and considerable detection in tumor tissues. Our findings indicate that coumarin-containing HA-based nanogels may be promising delivery systems for anticancer chemotherapy.