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目的制备新型右旋糖酐微凝胶偶联羟基喜树碱(HCPT)结合物,研究其体外释放及体内抗肿瘤活性。方法以大分子右旋糖酐为载体,己二酰肼为交联剂,同步接枝mPEG己二酰肼单腙、偶联羟基喜树碱丁二酸单酯,制备出以酰腙结构为连接键的纳米凝胶偶联HCPT。结果载药凝胶形成了内疏水外亲水的胶束结构,粒径约为100 nm,可实现对肿瘤组织的被动靶向;载药量达5.63%,药物释放符合Rc=Atn1/(B+Ctn2)动力学方程,在pH 5.4缓冲溶液中的释放速率比在pH 4.5和pH7.4缓冲液中的快;相同时间内纳米凝胶偶联药物的在小鼠体内的抑瘤率与羟基喜树碱相比优势不明显,但生存率明显提高。结论该纳米凝胶偶联物具有pH敏感性,可实验肿瘤组织的被动靶向释药,在小鼠体内毒性降低,呈现显著缓释特性,可望开发成新型高分子前药。
Objective To prepare a novel dextran microgel-conjugated hydroxycamptothecin (HCPT) conjugate to study its in vitro release and in vivo anti-tumor activity. Methods The macromolecular dextran as carrier and adipic dihydrazide as crosslinking agent were grafted simultaneously with mPEG adipoyl hydrazone monohydrazone and hydroxycamptothecin succinate respectively to prepare the acylhydrazone structure Nanogel-coupled HCPT. Results The drug-loaded gels formed an internally hydrophobically-hydrophobic micellar structure with a particle size of about 100 nm and achieved a passive targeting of the tumor tissue. The drug loading reached 5.63% and the drug release was in accordance with Rc = Atn1 / (B + Ctn2) kinetic equation, the release rate in pH 5.4 buffer solution is faster than in pH 4.5 and pH 7.4 buffer; the inhibition rate of nano-gel-coupled drug in mice at the same time is similar to that of hydroxyl Camptothecin compared with the obvious advantage, but significantly improved survival. CONCLUSIONS: The nanoconjugate conjugate has pH-sensitivity and can be used to experimentally target the release of tumor tissue in vivo. The toxicity of the nanoconjugate conjugate is reduced in vivo and shows a sustained release characteristic. It is expected to be developed into a new type of macromolecular prodrug.