Doxorubicin releasing PLGA/PMA microparticles for MT1-MMP targeting of hepatic cancer

초록

In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly(styrene-alt-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 ± 3 μm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/ pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1 %) and loading content (2.9 %). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (~25 % at pH 5.4 and ~8 % at pH 7.4) and accumulated significantly in an MT1-MMP-over-expressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 hrs after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC.