Studies On A54 Peptide Functionalized Poly(Lactic-co-glycolic Acid)-g-dextran Conjugate Micelles For Targeting Drug Delivery

Specific delivery of chemotherapy drugs and magnetic resonance imaging contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA self-assembled to form micelles with a low critical micelle concentration of 22.51 jig·mL-1 and diameter of about 50 nm. With doxorubicin (DOX) base as a model antitumor drug, the drug-encapsulation efficiency of DOX-loaded A54-Dex-PLGA micelles (A54-Dex-PLGA/DOX) reached up to 75%. In vitro DOX release from the A54-Dex-PLGA/DOX was prolonged to 72 hours. The A54-Dex-PLGA micelles presented excellent internalization ability into hepatoma cells (BEL-7402 cell line and HepG2 cell line) in vitro, and the internalization ability was better in BEL-7402 cell line. In vitro antitumor activity studies confirmed that A54-Dex-PLGA/DOX micelles suppressed tumor-cell (BEL-7402 cell) growth more effectively than Dex-PLGA micelles. Furthermore, in vivo biodistribution testing demonstrated that the A54-Dex-PLGA micelles had a higher distribution ability to BEL-7402 tumors than that to HepG2 tumors.Meanwhile, the synthetic A54-Dex-PLGA micelles can entrap superparamagnetic iron oxide nanoparticles (SPIO) as a contrast agent for MRI without influence on drug (doxorubicin) encapsulation capacity. The drug-encapsulation efficiency was about 80% and drug loading was about 3.8%. The DOX and SPIO loaded conjugate micelles with diameter about 100 nm had good dispersion. The DOX and SPIO loaded conjugate micelles could specific target BEL-7402 cell line. MTT assay and living cell staining method results showed that A54 modified drug loaded micelles had stronger antitumor effect (IC50 was approximately 0.56μg/mL) than that of unmodified micelles (IC50 of approximately 1.24μg/mL). MRI results also proved the specifically binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402 in vitro. The BEL-7402 orthotopic implantation model in vivo MR imaging experiments further validated the targeting effect of DOX and SPIO loaded conjugate micelles. In vivo anti-tumor activity results showed that A54-Dex-PLGA/DOX/SPIO micelles treatments suppressed tumor growth more effectively and reduced toxicity compared with commercial adriamycin injection. The research suggests that, with the mediation of homing peptide A54, the A54-Dex-PLGA carrier has promising potential in special tumor targeting, efficient therapy for tumor, systematic toxicity reduction and liver tumor targeting molecular imaging in MR. Multifunctional graft micelle delivery system A54-Dex-PLGA/DOX/SPIO was successfully constructed for tumor diagnosis and therapy.