Cisplatin-stitched alpha-poly(glutamatic acid) nanoconjugate for enhanced safety and effective tumor inhibition

摘要

Conjugation of cisplatin to macromolecular carriers has been extensively studied for reducing systemic side effects. Here, a cisplatin-stitched alpha-poly(glutamatic acid) nanoconjugate with reduced adverse reactions and effective anti-tumor efficacy was synthesized via ionic interaction between platinum ion of cisplatin with carboxylic groups of alpha-poly(glutamatic acid). The nanoconjugate exhibited good water solubility, suitable size and polydispersity, almost spherical morphologies, and a sustained release profile without burst release. In vitro cytotoxicity and cell apoptosis assays performed in MCF-7 cells showed significantly decreased cytotoxicity of nanoconjugate compared with free cisplatin, and larger ratio of early apoptosis than late apoptosis. Quantitative cellular uptake assay also supported that conjugation of cisplatin to a-poly(glutamatic acid) reduced its cytotoxicity. Further studies revealed that the unique space structure of nanoconjugate acted as a shield for cisplatin against GSH detoxification under physiological conditions. In vivo studies regarding maximum tolerated dose, hematological parameters evaluation and histopathology assay demonstrated the superior safety of nanoconjugates. Furthermore, the nanoconjugates also achieved comparable antitumor efficacy with no apparent weight loss and death at a high equivalent cisplatin dose of 25 mg/kg. Moreover, the survival rate of mice treated with nanoconjugate was greatly larger than that of free cisplatin. These findings suggest that the cisplatin-stitched alpha-poly(glutamatic acid) nanoconjugate may hold great potential in clinical application for cancer therapy.