Self-assembling doxorubicin-prodrug nanoparticles as siRNA drug delivery system for cancer treatment: in vitro and in vivo†
Abstract
Co-delivery of siRNAs and chemotherapeutic drugs to kill tumors have achieved superior tumor growth inhibition. However, due to siRNAs and chemotherapeutic drugs with different molecular properties, co-delivery carriers use more cationic materials to bind siRNAs and excessive inert materials to embed drugs, causing low drug-loading contents and systemic toxicity. To achieve this goal, doxorubicin (DOX) is chemically conjugated to stearoyl chloride (C18) through N-methyldiethanol amine (N) as cross-linker to form amphiphilic C18–N–DOX. C18–N–DOX contains a tertiary amine that can complex siRNAs at low pH (pH 3) and reduce the density of the positive charges on the surface of NPs at physiological pH (pH 7.4). C18–N–DOX, together with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000) DSPE-PEG2000, self-assemble into DOX-prodrug nanoparticles (DOX-prodrug NPs), which bind siRNAs in citrate buffer (pH 3) to form DOX-prodrug NPs/siRNA. After replacing citrate buffer (pH 3) with PBS (pH 7.4), DOX-prodrug NPs/siRNA have slight negative charges due to complexed more siRNAs. In this study, clear evidence is shown that DOX-prodrug NPs can deliver siRNA to the same tumor cells both in vitro and in vivo. Moreover, DOX-prodrug NPs/siRNA show a great effect on inhibiting tumor cell growth both in vitro and in vivo. Therefore, the DOX-prodrug NPs are promising candidates as siRNAs delivery system for tumor therapy.