ABSTRACT
An innovative hyaluronan-based nano-delivery system is proposed for the active targeting towards ER+ breast cancer. Hyaluronic acid (HA), an endogenous and bioactive anionic polysaccharide, is functionalized with estradiol (ES), a sexual hormone involved in the development of some hormone-dependent tumors, to give an amphiphilic derivative (HA-ES) able to spontaneously self-assemble in water to form soft nanoparticles or nanogels (NHs). The synthetic strategy used to obtain the polymer derivatives and the physico-chemical properties of the obtained nanogels (ES-NHs) are reported. ES-NHs ability to entrap hydrophobic molecules has also been investigated, by loading curcumin (CUR) and docetaxel (DTX), both able to inhibit the growth of ER+ breast cancer. The formulations are studied for their capability to inhibit the growth of the MCF-7 cell line, thus evaluating their efficacy and potential as a selective drug delivery systems. Our results demonstrate that ES-NHs have not toxic effects on the cell line, and that both ES-NHs/CUR and ES-NHs/DTX treatments inhibit MCF-7 cell growth, with ES-NHs/DTX effect higher than that of free DTX. Our findings support the use of ES-NHs to deliver drugs to ER+ breast cancer cells, assuming a receptor-dependent targeting.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Curcumin , Nanoparticles , Humans , Female , Drug Carriers/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Hyaluronic Acid/chemistry , Nanogels/therapeutic use , Estradiol/pharmacology , Docetaxel/therapeutic use , Drug Delivery Systems , Curcumin/chemistry , MCF-7 Cells , Nanoparticles/chemistry , Cell Line, Tumor , Antineoplastic Agents/chemistryABSTRACT
Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach.
Subject(s)
Drug Carriers/chemistry , Nanogels/chemistry , Polysaccharides/chemistry , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , Carbohydrate Sequence , Drug Carriers/pharmacology , Drug Compounding/methods , Gene Transfer Techniques , Humans , Hydrophobic and Hydrophilic Interactions , Immunity/drug effects , Microfluidics/methods , Polysaccharides/pharmacology , Static Electricity , Vaccines, Synthetic/chemistryABSTRACT
Interpenetrated polymer network microgels, composed of crosslinked networks of poly(N-isopropylacrylamide) and polyacrylic acid (PAAc), have been investigated through rheological measurements at four different amounts of PAAc. Both PAAc content and crosslinking degree modify particle dimensions, mass and softness, thereby strongly affecting the volume fraction and the system viscosity. Here the volume fraction is derived from the flow curves at low concentrations by fitting the zero-shear viscosity with the Einstein-Batchelor equation which provides a parameterkto shift weight concentration to volume fraction. We find that particles with higher PAAc content and crosslinker are characterized by a greater value ofkand therefore by larger volume fractions when compared to softer particles. The packing fractions obtained from rheological measurements are compared with those from static light scattering for two PAAc contents revealing a good agreement. Moreover, the behaviour of the viscosity as a function of packing fraction, at room temperature, has highlighted an Arrhenius dependence for microgels synthesized with low PAAc content and a Vogel-Fulcher-Tammann dependence for the highest investigated PAAc concentration. A comparison with the hard spheres behaviour indicates a steepest increase of the viscosity with decreasing particles softness. Finally, the volume fraction dependence of the viscosity at a fixed PAAc and at two different temperatures, below and above the volume phase transition, shows a quantitative agreement with the structural relaxation time measured through dynamic light scattering indicating that interpenetrated polymer network microgels softness can be tuned with PAAc and temperature and that, depending on particle softness, two different routes are followed.
ABSTRACT
Hyaluronan (HA) is among the most used biopolymers for viscosupplementation and dermocosmetics. However, the current injectable HA-based formulations present relevant limitations: I) unmodified HA is quickly degraded by endogenous hyaluronidases (HAase), resulting in short lasting properties; II) cross-linked HA, although shows enhanced stability against HAase, often contains toxic chemical cross-linkers. As such, herein, we present biocompatible self-assembled hyaluronan-cholesterol nanohydrogels (HA-CH NHs) able to bind to HAase and inhibit the enzyme activity in vitro, more efficiently than currently marketed HA-based cross-linked formulations (e.g. Jonexa™). HA-CH NHs inhibit HAase through a mixed mechanism, by which NHs bind to HAase with an affinity constant 7-fold higher than that of native HA. Similar NHs, based on gellan-CH, evidenced no binding to HAase, neither inhibition of the enzyme activity, suggesting this effect might be due to the specific binding of HA-CH to the active site of the enzyme. Therefore, HA-CH NHs were engineered into injectable hybrid HA mixtures or physical hydrogels, able to halt the enzymatic degradation of HA.
