am508262j_si_001.pdf (240.94 kB)
Delivery of Mitogen-Activated Protein Kinase Inhibitor for Hepatocellular Carcinoma Stem Cell Therapy
journal contribution
posted on 2015-01-14, 00:00 authored by Yang Liu, Xin Wang, Chun-Yang Sun, Jun WangHepatocellular
carcinoma (HCC) is one of the most common malignant
human tumors worldwide, but no effective therapeutic options are currently
available. The cancer stem cell (CSC) has proven to play a central
role in the development, metastasis, and recurrence of HCC. In this
study, we report a dual functional mitogen-activated protein kinase
inhibitor (U0126)-based therapy for treating both bulk HCC and HCC
CSCs, using poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as
the drug carrier. It is demonstrated that nanoparticle encapsulation
enhanced the cell uptake of U0126 in HCC CSCs and that enhanced endocytosis
lead to augmented cytotoxicity of U0126 in HCC CSCs. Moreover, the
nanoparticle encapsulation increased the inhibition of self-renewal
capability, prolonged the circulation time, and increased the tumor
accumulation of U0126 when compared with the use of the free inhibitor.
The systemic delivery of U0126 remarkably enhanced the suppression
of tumor development with decreased CSCs in the HepG2 xenograft simultaneously
with reduced systemic toxicity.