Nanogels (NGs) have attracted great attention because of their outstanding biocompatibility, biodegradability, very low toxicity, flexibility, and softness. NGs are characterized with a low and nonspecific interaction with blood proteins, meaning that they do not induce any immunological responses in the body. Due to these properties, NGs are considered promising candidates for pharmaceutical and biomedical application. In this work, we introduce the development of novel functional nanogel obtained from two naturally based products—citric acid (CA) and pentane-1,2,5-triol (PT). The nanogel was synthesized by precipitation esterification reaction of CA and PT in tetrahydrofuran using N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide (EDC) and 4-(dimethylamino)pyridine (DMAP) catalyst system. Dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM) analyses revealed formation of spherical nanogel particles with a negative surface charge. Next, the nanogel was loaded with doxorubicin hydrochloride (DOX) by electrostatic interactions between carboxylic groups present in the nanogel and amino groups of DOX. The drug-loaded nanogel exhibited high encapsulation efficiency (EE~95%), and a bi-phasic release behavior. Embedding DOX into nanogel also stabilized the drug against photodegradation. The degradability of nanogel under acidic and neutral conditions with time was investigated as well.
Nanogels are attractive drug delivery systems that provide high loading capacity for drug molecules, improve their stability, and increase cellular uptake. Natural antioxidants, especially polyphenols such as resveratrol, are distinguished by low aqueous solubility, which hinders therapeutic activity. Thus, in the present study, resveratrol was incorporated into nanogel particles, aiming to improve its protective effects in vitro. The nanogel was prepared from natural substances via esterification of citric acid and pentane-1,2,5-triol. High encapsulation efficiency (94.5%) was achieved by applying the solvent evaporation method. Dynamic light scattering, atomic force microscopy, and transmission electron microscopy revealed that the resveratrol-loaded nanogel particles were spherical in shape with nanoscopic dimensions (220 nm). In vitro release tests showed that a complete release of resveratrol was achieved for 24 h, whereas at the same time the non-encapsulated drug was poorly dissolved. The protective effect of the encapsulated resveratrol against oxidative stress in fibroblast and neuroblastoma cells was significantly stronger compared to the non-encapsulated drug. Similarly, the protection in a model of iron/ascorbic acid-induced lipid peroxidation on rat liver and brain microsomes was higher with the encapsulated resveratrol. In conclusion, embedding resveratrol in this newly developed nanogel improved its biopharmaceutical properties and protective effects in oxidative stress models.
We report the elaboration of redox-responsive functional micellar nanocarriers designed for triggered release of caffeic acid phenethyl ester (CAPE) in cancer therapy. Three-layered micelles, comprising a poly(ε-caprolactone) (PCL) core, a middle poly(acrylic acid)/poly(ethylene oxide) (PAA/PEO) layer and a PEO outer corona, were prepared by co-assembly of PEO113-b-PCL35-b-PEO113 and PAA13-b-PCL35-b-PAA13 amphiphilic triblock copolymers in aqueous media. The preformed micelles were loaded with CAPE via hydrophobic interactions between the drug molecules and PCL core, and subsequently crosslinked by reaction of carboxyl groups from PAA and a disulfide crosslinking agent. The reaction of crosslinking took place in the middle layer of the nanocarriers without changing the encapsulation efficiency (EE~90%) of the system. The crosslinked polymeric micelles (CPMs) exhibited superior structural stability and did not release CAPE in phosphate buffer (pH 7.4). However, in weak acidic media and in the presence of 10 mM reducing agent (dithiothreitol, DTT), the payload was released at a high rate from CPMs due to the breakup of disulfide linkages. The physicochemical properties of the nanocarriers were investigated by dynamic and electrophoretic light scattering (DLS and ELS) and atomic force microscopy (AFM). The rapid release of CAPE under intracellular-like conditions and the lack of premature drug release in media resembling the blood stream (neutral pH) make the developed CPMs a promising candidate for controllable drug release in the microenvironment of tumors.
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