Abstract
ABSTRACT Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer. General chemotherapy and radiotherapy offer somewhat unsatisfactory responsiveness, the overall recurrence rate is very high, this could be attributed to the chemotherapeutic resistance that results from tumor hypoxia. Recently, hypoxia has been described as an important factor to chemotherapeutic resistance, owing to the redox state, meaning that oxygen (O2) is required to generate ROS to be maximally cytotoxic. To address the above issue, an oxygen generating system was fabricated using alginate, having calcium peroxide as the oxygen generating source, which decompose hydrogen peroxide and release oxygen when contact with water. The decomposition rate could be increased by the addition of catalase, a common enzyme found in nearly all living organisms. This novel system was performed under two controlled conditions, normoxia and hypoxia. Optimization of microspheres, cytotoxicity of material and condition of the system were carried out specifically based on the responses observed from in vitro studies using Hep3B cells as a candidate. Microspheres are capable of sustainably release oxygen over 24 hours while the best cross-linking time during the gelation was found to be 10 minutes. It was observed that cells maintained high viability under hypoxic condition and found that doxorubicin-induced oxyradicals play a vital role in the development of drug resistance. However, this oxygen generating system has successfully reduced the chemotherapeutic resistance which induced by hypoxia and enhanced the chemotherapeutic efficacy of doxorubicin. These results suggest that the developed oxygen generating system is a highly promising approach in maximizing the therapeutic effectiveness with minimal side effects. Keywords: hypoxia; chemotherapeutic resistance; oxygen generating system; redox cycle of doxorubicin; enhancement of the chemotherapeutic efficacy