MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-co-glycolic Acid)/Poly(styrene-alt-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer

Abstract

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-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h 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.

Recent Advances on Polymeric Beads or Hydrogels as Embolization Agents for Improved Transcatheter Arterial Chemoembolization (TACE)

“…Last but not least, functional peptide could also be conjugated to polymeric microparticles for targeted delivery of embolization beads. As a typical example, Davaa et al (2017) linked matrix metalloproteinase responsive peptide (MT1-MMP binding peptide) to poly(lactic- co -glycolic acid/poly-(styrene-alt-maleic anhydride) (PLGA/pSMA) microspheres, which exhibited enhanced accumulation in MT1-MMP overexpressing Hep3B cells, as shown in Figure 6B. More interestingly, these peptide conjugated microspheres could accumulate in hepatic vessels for up to 24 h without undesired diffusion to lung, and they significantly inhibited the tumor growth in a Hep3B xenografted mice model.…”

“…(B) Synthesis of tumor targeting PLGA/pSMA microspheres with conjugation of MT1-MMP binding peptide and chemotherapeutic doxorubicin, for more precise transarterial chemoembolism therapy. [Reproduced with permission from Davaa et al (2017), Copyright 2017 American Chemical Society].…”

Microfluidics for core–shell drug carrier particles – a review

“…Also, healthy cells are exposed to drugs' cytotoxic effects, and an inadequate portion of the applied drug arrives at the tumor position in most cases. 5,[54][55][56] In addition, there is a need for high drug dosage, and it is another unwanted side effect. So, new drug delivery technologies need to be promoted to solve these limitations and improve cancer therapies' potency.…”

“…Nanoparticles are one of the most widely used carriers that, due to their ability to achieve therapeutic targets at acceptable times and doses, have a great interest in their potential in drug delivery. 5,56,58…”

“…71 There are two different types of release: delayed and stable. 56,61,65 The rst type referred to the release of active compounds with the delay in the desired location. There are many examples of delayed-release core-shell particles like encapsulated probiotics and tablets protected in the stomach against gastric acid by encapsulating them and releasing them in the small or large intestine.…”