刺激响应共负载药物/基因微载体的制备

Stimulus-responsive Polyplexes with Drug and Gene Co-Delivery

合成了聚乙烯亚胺接枝二茂铁(PEI-Fc)两亲聚合物,采用水包油法制备包埋疏水性抗癌药阿霉素(DOX)的载药胶束,并利用胶束表面正电荷的PEI链段有效缔合DNA,获得尺寸合适、表面带正电荷的阿霉素与基因共负载微载体.在磷酸盐(PBS)缓冲溶液中,共负载微载体能够缓慢释放出DOX.在硝酸铈铵存在下,二茂铁从疏水性转变为亲水性,使载药胶束完全解离,由于PEI-Fc与DNA之间的静电作用,使基因超分子组装体稳定存在,显示出很好的氧化响应特性.细胞培养结果表明,表面带正电荷的共负载微载体易被HepG2细胞内吞,并可转染,且随着DOX的释放逐渐杀死HepG2肝癌细胞,为安全稳定、具有刺激响应的药物与基因共负载微载体的制备提供了可行的途径.

With the rapid development of modern gene technology and the achievement of human genome project,new understanding of the cause and treatment of various diseases comes to us.It is one of the hot spot of scientific research that construction of drug and gene co-delivery system to achieve effective treatment of cancer.In this research,the amphiphilic graft polymer polyethyleneimine-ferrocene（PEI-Fc） was synthesized as drug and gene carrier.PEI-Fc could form micelles in aqueous solution through the hydrophobic side groups of ferrocene.The hydrophobic anticancer drug doxorubicine（DOX） was loaded in micelles by oil/water（O/W） method.The size of micelles increased from 21 nm to 43 nm.Then,DOX and gene co-delivery nanoparticles were successfully constructed via electrostatic interaction of the PEI chains in the shell and DNA molecule.This doxorubicine and gene co-delivery complexes had a suitable size and positive surface charge.The co-delivery complexes could release DOX slowly in PBS buffer solution.Ferrocene was transformed from hydrophobic group to hydrophilic group with the adding of ceric ammonium nitrate.It leaded to the completely disruption of DOX-loaded micelles.Due to electrostatic interaction of PEI and DNA,the gene supramolecular complexes remained stable existence and showed commendable oxidation responsiveness.The consequences of in vitro cell culture experiments indicated that the co-delivery nanoparticles with positive charge were easily uptake by HepG2 cells and the cancer cells were killed with the sustaining release of DOX.And the PEI-Fc/DOX/DNA co-delivery nanoparticles in the cells could be transferred.In summary,the PEI-Fc/DOX/DNA co-delivery nanoparticles with redox stimulate-response could have potential use in clinical cancer therapy.