Abstract
Asiatic acid (AA), a natural triterpene found in Centalla asiatica, possesses polypharmacological properties that can contribute to the treatment and prophylaxis of various diseases. However, its hydrophobic nature and rapid metabolic rate lead to poor bioavailability. The aim of this research was to develop a thermoresponsive nanogel from hyaluronic acid (HA) for solubility and stability enhancement of AA. Poly(N-isopropylacrylamide) (pNIPAM) was conjugated onto HA using a carbodiimide reaction followed by 1H NMR characterization. pNIPAM-grafted HA (HA-pNIPAM) nanogels were prepared with three concentrations of polymer, 0.1, 0.15 and 0.25% w/v, in water by the sonication method. AA was loaded into the nanogel by the incubation method. Size, morphology, AA loading capacity and encapsulation efficiency (EE) were analyzed. In vitro cytocompatibility was evaluated in fibroblast L-929 cells using the PrestoBlue assay. Single-dose toxicity was studied using rats. HA-pNIPAM nanogels at a 4.88% grafting degree showed reversible thermo-responsive behavior. All nanogel formulations could significantly increase AA water solubility and the stability was higher in nanogels prepared with high polymer concentrations over 180 days. The cell culture study showed that 12.5 µM AA in nanogel formulations was considered non-toxic to the L-929 cells; however, a dose-dependent cytotoxic effect was observed at higher AA-loaded concentrations. In vivo study proved the non-toxic effect of AA loaded in HA-pNIPAM nanogels compared with the control. Taken together, HA-pNIPAM nanogel is a promising biocompatible delivery system both in vitro and in vivo for hydrophobic AA molecules.
Highlights
Asiatic acid (AA) is one of the major bioactive triterpenes present in Centella asiatica, whose common names are pennywort and gotu koka [1]
Polymer concentrations of 0.1, 0.15 and 0.25% w/v were used to form nanogel formulations designated as hyaluronic acid (HA)-pNIPAM 0.1, HA-pNIPAM 0.15 and HA-pNIPAM 0.25, respectively
We further investigated whether treatments cause a change in hematological parameters, including white blood cells (WBCs), neutrophils, lymphocytes, monocytes, eosinophils, red blood cells (RBCs), hemoglobin, hematocrit, mean cell hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and platelets
Summary
Asiatic acid (AA) is one of the major bioactive triterpenes present in Centella asiatica, whose common names are pennywort and gotu koka [1]. AA possesses anti-oxidative, anti-inflammatory [2,3,4,5], anticancer [6,7,8], antifungal [9], antimicrobial [10,11], antidiabetic and antihyperlipidemic activities [12]; and cardiac, renal, hepatic and neuroprotective 4.0/). It has the potential to inhibit osteoporosis [18,19] and fibrotic diseases [13,20,21], and to induce collagen synthesis and wound healing [22]. AA is highly lipophilic (log p value, 5.7), poorly soluble in water (0.0598 mg/L at 25 ◦ C) and undergoes rapid metabolism by the liver. Studies have demonstrated the therapeutic activities of AA against many diseases, the limitations of poor bioavailability and rapid metabolism hinder this compound from developing into therapeutic applications [23]. There are several approaches for delivery of insoluble drugs, such as the prodrug strategy [24], pH modification using a pH modifier and salt form, co-solvency, surfactant solubilization, amorphous formation, solid dispersions, cocrystals, nanoparticle delivery systems consisting of polymeric micelles, nanocrystals, nanosuspensions, solid lipid nanoparticles, liposomes, microemulsions and self-emulsifying drug delivery systems [25]
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