Abstract
The objective of this study aimed to develop biodegradable calcium alginate microspheres carrying doxorubicin (Dox) at the micrometer-scale for sustained release and the capacity of pH regulatory for transarterial chemoembolization. Ultrasonic atomization and CaCl2 cross-linking technologies were used to prepare the microspheres. A 4-by-5 experiment was first designed to identify imperative parameters. The concentration of CaCl2 and the flow rate of the pump were found to be critical to generate microspheres with a constant volume median diameter (~39 μm) across five groups with different alginate: NaHCO3 ratios using each corresponding flow rate. In each group, the encapsulation efficiency was positively correlated to the Dox-loading %. Fourier-transform infrared spectroscopy showed that NaHCO3 and Dox were step-by-step incorporated into the calcium alginate microspheres successfully. Microspheres containing alginate: NaHCO3 = 1 exhibited rough and porous surfaces, high Young’s modulus, and hardness. In each group with the same alginate: NaHCO3 ratio, the swelling rates of microspheres were higher in PBS containing 10% FBS compared to those in PBS alone. Microspheres with relatively high NaHCO3 concentrations in PBS containing 10% FBS maintained better physiological pH and higher accumulated Dox release ratios. In two distinct hepatocellular carcinoma-derived cell lines, treatments with microspheres carrying Dox demonstrated that the cell viabilities decreased in groups with relatively high NaHCO3 ratios in time- and dose-dependent manners. Our results suggested that biodegradable alginate microspheres containing relatively high NaHCO3 concentrations improved the cytotoxicity effects in vitro.
Highlights
Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-associated mortality worldwide and the incidence continues to increase [1]
No significant difference was found within groups for each parameter while significant differences were identified for the concentration of CaCl2 and flow rate (Table 1)
Among several groups with different alginate:NaHCO3 ratios, flow rates were optimized in each group
Summary
Hepatocellular carcinoma (HCC) is one of the foremost causes of tumor-associated mortality worldwide and the incidence continues to increase [1]. HCC is usually diagnosed at intermediate or advanced stages while merely palliative remedies could be used, leading to poor overall survival. Transarterial chemoembolization (TACE) is a frequently recommended treatment for asymptomatic, multifocal, and/or large HCC devoid of macrovascular invasion or metastasis [2,3]. TACE intends to induce tumor neurosis, resulting in cytotoxic effects along with ischemia in the tumor tissue. Chemoembolization, especially using Doxorubicin (Dox), improved the survival of stringently selected patients with unresectable hepatocellular carcinoma [2]. Numerous types of microspheres including temporary or permanent are commercially available for TACE. The most commonly used are DC BeadTM [4] and HapaSphereTM [3]
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