Theranostic pH responsive doxorubicin loaded nanoparticles inducing active targeting and apoptosis for advanced gastric cancer

摘要

Advanced gastric cancer (AGC) has a low remission rate and short progression. Resistance to chemotherapy in AGC is attributed to poor tissue penetration. This study developed multifunctional magnetic-polymer nanocarriers (MNPs) with folate receptor (FR)-targeting and pH-sensitivity to carry doxorubicin (DOX) to treat AGC. Avoiding commonly used polymeric and non-organic coating on MNPs, folic acid conjugated, pH-sensitive amphiphilic poly (β-aminoester) self-assemble with hydrophobic oleic acid modified magnetic nanoparticles and the resulted hydrophobic interaction area is a reservoir for lipophilic DOX (F-P-DOX (with folic acid conjugated, P-DOX (without folic acid)). After study of release profile in response to pH stimuli, before cellular study, we verified the expression of FR in BGC823 and SGC7901 gastric cancer cells using Western blotting. Confocal microscopy illustrated a higher efficiency of cellular intemalization at pH 6.5 than at pH 7.4 after 12 h incubation of either P-DOX or F-P-DOX. Furthermore, F-P-DOX was internalized by GC cells more efficiently than P-DOX. MTT assay showed a higher cytotoxicity of F-P-DOX than free DOX and P-DOX under different doses. F-P-DOX induced apoptosis of GC cells were revealed from the lipid droplet and compacted nuclear chromatin using transmission electron microscope and the elevated mRNA level of Caspase 3 by real-time polymerase chain reaction. On xenograft GC model, F-P-DOX suppressed tumor growth more effectively than free DOX and P-DOX without causing obvious adverse consequences. Meanwhile, MRI presented that F-P-DOX accumulated at the tumor site. Taken together, these observations suggest F-P-DOX is a promising theranostic candidate for FR-posilive GC.