PEG修饰方式对磁性靶向酶解前药策略治疗前列腺癌效果影响的实验研究

Targeted delivery of prodrug activating enzyme is the prerequisite of magnetic directed enzyme/prodrug therapy(MDEPT) strategy for prostate cancer.Our previous study showed that the immobilized β-Glucosidase,the activating enzyme of prodrug amygdalin, could be selectively delivered to subcutaneous tumor location by magnetic targeting.However,the quantity of delivered enzyme could not reach the order of magnitude for inihibition of tumor growth. Polyethylent glycol(PEG) modification may improve the plasma stability of magnetic nanoparticles,thereby,improve the delivery efficiency of enzyme.Accordingly,we try to find the optimal couple methode of magnetic nanopartles,β-Glu and PEG,furtherly accomplish MDEPT strategy of prostate cancer.In the study,the magnetic nanoparticles,β-Glu and PEG were coupled by chemical coupling methods.The PEG-modified,β-Glu immobilized magnetic nanoparticles were characterized by magnetization measurement,enzyme activity analysis and pharmacokinetics methods.The magnetic resonance imaging and analysis of enzyme activity in tumor tissue were used to evaluate the delivery efficiency in order to identify the optimal modification methode of enzyme loaded nanoparticles.Cancer cell and subcutaneous tumor growth inhibition experiment were used to identified the inhibition effect of MDEPT to prostate cancer.This study would provide animal experiment basis and rationale for MDEPT of prostate cancer,and provide firenew thinking methods for prostate cancer target drug chemotherapy.

通过磁性纳米粒子向肿瘤部位传送前药激活酶是实现前列腺癌磁性靶向酶解前药治疗（MDEPT）策略的前提。我们前期研究发现：β-葡萄糖苷酶可以通过磁性靶向被传送到肿瘤部位，但不能达到激活苦杏仁甙抑制肿瘤的数量级。PEG(聚乙二醇)修饰可以提高磁性纳米粒子的稳定性从而提高其靶向传送酶效率。因此，我们试图找到磁性纳米粒子偶联β-葡萄糖苷酶及PEG的最佳方式，并进一步实现前列腺癌的磁性靶向酶解前药治疗策略。本项目拟采用化学偶联的方法偶联磁性纳米粒子、β-葡萄糖苷酶及PEG；通过磁顺应性测定、酶活测定及药代动力学分析等方法对载酶粒子进行质量鉴定；进一步采用磁共振显像及组织酶活性测定评价其载酶效率并由此得到载酶粒子的最佳修饰方式；最后通过细胞实验及裸鼠肿瘤抑制实验明确MDEPT策略对前列腺癌生长的抑制作用，从而为该策略治疗前列腺癌提供动物实验基础及理论依据，为前列腺癌靶向治疗研究提供新的思路和方法。