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A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)₂ and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of <b>4d</b>, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.1 <i>w</i>/<i>w</i>), was the most stable. Furthermore, the liposomes of compound <b>4d</b> (8 mg/kg, 4 times) and higher dose of compound <b>4d</b> (24 mg/kg, 4 times) showed better therapeutic effect than paclitaxel (8 mg/kg, 4 times) in the 4T1 tumor model in vivo, and the rates of tumor inhibition were 74.3%, 81.9% and 58.5%, respectively. This study provided a reasonable design strategy for the insoluble drugs to improve their drug loading into liposomes and anti-tumor effect in vivo.