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Our research group has recently developed microparticles of a hyaluronic acid derivative used for bottom-up growth of microparticles/human mesenchymal stem cells (hMSCs). In this work, we investigated a strategy to increase the stiffening of aggregated constructs between microparticles and hMSCs. In particular, we applied a Michael-type crosslinking procedure between microparticles to allow a chemically driven and cell-compatible stiffening of constructs. Two batches of microparticles were functionalized with thiol and maleimide groups, respectively, and were then mixed to allow chemical crosslinking. The adhesion of hMSCs was controlled through addition of the adhesive peptide cyclo(-Arg-Gly-Asp-D-Phe-Cys) (cyRGDC). Rheological measurements performed in this study showed that the chemical stiffening strategy allows the G ' modulus of bottom-up growing constructs to be increased, while viability tests suggest that the chemical procedure did not negatively affect cell viability compared with constructs obtained without chemical crosslinking. (c) 2018 Society of Chemical Industry

Topically administered ocular Drug Delivery Systems are the most desirable formulations for the treatment of ocular chronic diseases, being the most simple, convenient and patient-friendly ocular route of administration, despite it requires prolonged and continuous treatment over time. At this regard, ocular insert represent an innovative and effective strategy. Ocular inserts are solid/semisolid sterile preparations characterized by dimensions and shape specifically designed for topical ocular administration. They are able to rapidly adhere on the ocular surface and remain in situ for prolonged period while assuring a controlled drug release and potentially increasing drug transcorneal absorption. Based on these assumptions, the aim of this work was to opportunely design and characterize novel useful polymeric inserts based on a 3D scaffold. Poly-butylene succinate (PBS) scaffolds were prepared by electrospinning, functionalized with biopolymers (inulin, poly(hydroxyethyl)aspartamide [PHEA], heparin) by plasma-assisted reaction and loaded with triamcinolone acetonide (TA). The obtained products were evaluated in terms of physico-chemical, technological-applicative and biological properties. Ocular inserts resulted non-bioerodible, with a very low swelling degree and a high drug loading ability, cytocompatible and extremely mucoadhesive. Moreover, inserts are also able to slowly release TA after firmly adhering on the corneal tissue. This translates into a significant increase of transcorneal permeation and penetration (enhancement of both Kp and Ka values up to an order magnitude). In conclusion, inserts can be an effective strategy to increase patient compliance by reducing the frequency of administration and avoiding pulsatile drug entry into the eye.

Two derivatives of hyaluronic acid (HA) have been synthesized by atom transfer radical polymerization (ATRP), starting from an ethylenediamino HA derivative (HA-EDA) and by using diethylaminoethyl methacrylate (DEAEMA) as a monomer for polymerization. Both samples, indicated as HA-EDA-pDEAEMA a and b, are able to condense siRNA, as determined by gel retardation assay and resulting complexes show a size and a zeta potential value dependent on polymerization number, as determined by dynamic light scattering measurements. In vitro studies performed on HCT 116 cell line, that over express CD44 receptor, demonstrate a receptor mediated uptake of complexes, regardless of their surface charge. New cationic HA derivatives (HA-EDA-pDEAEMA), synthesized by atom transfer radical polymerization (ATRP) are able to complex siRNA and to form self-assembled nanosystems. In vitro studies performed on HCT 116 cell line, which over express CD44 receptor, demonstrate a receptor-mediated uptake of complexes.

SIMPLE, BIOCOMPATIBLE AND COST-EFFECTIVE INULIN BASED siRNA DELIVERY SYSTEMS

Background: In hepatocellular carcinoma (HCC), different signaling pathways are de-regulated, and among them, the expression of the epidermal growth factor receptor (EGFR). Tyrphostin AG-1478 is a lipophilic low molecular weight inhibitor of EGFR, preferentially acting on liver tumor cells. In order to overcome its poor drug solubility and thus improving its anticancer activity, it was entrapped into nanostructured lipid carriers (NLC) by using safe ingredients for parenteral delivery. Results: Nanostructured lipid carriers (NLC) carrying tyrphostin AG-1478 were prepared by using the nanoprecipitation method and different matrix compositions. The best system in terms of mean size, PDI, zeta potential, drug loading and release profile was chosen to evaluate the anti-proliferative effect of drug-loaded NLC versus free drug on human hepatocellular carcinoma HA22T/VGH cells. Conclusions: Thanks to the entrapment into NLC systems, tyrphostin AG-1478 shows an enhanced in vitro anti-tumor activity compared to free drug. These finding raises hope of future drug delivery strategy of tyrphostin AG-1478 -loaded NLC targeted to the liver for the HCC treatment.

Polymer coated gold nanospheres are proposed as a tumor selective carrier for the anticancer drug doxorubicin. Thiolated polyethyleneglycol (PEG-SH) and an inulin-amino derivative based copolymer (INU-EDA) were used as stabilizing and coating materials for 40 nm gold nanospheres. The resulting polymer coated gold nanospheres (Au@PEG-INU) showed excellent physicochemical stability and potential stealth like behavior. The system was loaded with doxorubicin (Au@PEG-INU/Doxo) and its cytotoxicity profile was evaluated on human cervical cancer cells (HeLa) and lung cancer cells (A549), as compared to Au@PEG-INU and doxorubicin alone. Cytotoxicity assays showed that the system is able to drastically reduce cell viability upon incubation for 3 days. This result was supported by the ability of Au@PEG-INU/Doxo to be internalized by cancer cells and to release doxorubicin, as assessed by fluorescence microscopy. Finally, a cancer/non cancer cell co-culture model was used to display the advantageous therapeutic effects of the proposed system with respect to doxorubicin alone, thereby demonstrating the ability of Au@PEG-INU/Doxo to preferentially accumulate in tumor cells due to their enhanced metabolism, and to selectively kill target cells. ¸ The Royal Society of Chemistry 2016.