Synthesis and cytotoxicity evaluation of doxorubicin-polyethyleneimine conjugate as a potential carrier for dual delivery of drug and gene

Doxorubicin is a wide spectrum chemotherapeutic agent which is used mostly in leukemia and solid tumors. Its therapeutic effects have been limited by its dose-dependent cardiotoxicity and multi drug resistance (MDR). One of the promising strategies to overcome MDR is co-delivery of the drug with the genes that can silence overexpression of P-glycoprotein on the tumor cell. In this study, a drug-polymer conjugate using polyethyleneimine as a gene carrier and the chemotherapeutic agent, doxorubicin was synthesized and evaluated. The conjugation of doxorubicin to polyethyleneimine was performed using N-(9-fluroenylmethoxycarbonyl)-DOX-14-O-sccinate, an ester derivative of doxorubicin. Drug release of conjugate was slower than doxorubicin solution of the marketed formulation. Capability of this carrier for delivery of a reporter gene was also examined and confirmed by determination of buffering capacity, gel retardation and DNase protection assays. Cytotoxicity study of conjugate on HepG2 cells showed higher toxicity in lower concentration compared to free doxorubicin. This lower concentration provides possibility of using low dose of drug and lower incidence of adverse effects. Since PEI is known as the golden standard of gene delivery, by co-delivery of drug and a gene that silences P-glycoprotein, this conjugate can be suggested as a dual delivery carrier in order to obtain doxorubicin cytotoxic efficacy as well as reduction of multi drug resistance in tumor cells. [Display omitted]