Poly （amidoamine） dendrimers are emerging as versatile and derivatizable nano-scale drug delivery vehicles. In our study, cis-4,7,10,13,16,19-docosahexenoic acid and doxorubicin were conjugated to generation 2.5 PAMAM. The molecular architecture of the carrier was designed for optimized blood circulation and optimized drug release through the use of pH-sensitive hydrazone linkages. In vitro, DHA-PAMAM-DOX conjugates were able to release twice as much doxorubicin at pH 4.5 （lysosomal pH） as at pH 7.4, ensuring more pronounced antitumor activity. Upon intravenous administration to ICR mice, the DHA-PAMAM-DOX delivery systems resulted in more plasma exposure of doxorubicin than free doxorubicin solution. In efficacy studies performed with B6D2F1 mice bearing B16 melanoma tumors, DHA-PAMAM-DOX was significantly more efficient in inhibiting tumor growth than free doxorubicin at the dose equivalent to 5 mg/kg doxorubicin. Our research provides evidence that DHA-PAMAM-DOX conjugates have the potential to enhance the effect of cancer therapy in the course of delivering anticancer drugs to their target sites.
