Journal of Cancer Research and Clinical Oncology (2018) 144:1463–1473
ORIGINAL ARTICLE – CANCER RESEARCH
Hyaluronic acid-modiﬁed polyamidoamine dendrimer G5-entrapped
gold nanoparticles delivering METase gene inhibits gastric tumor
growth via targeting CD44+ gastric cancer cells
· Hou‑Ting Zhang
· Lin Xin
Received: 21 January 2018 / Accepted: 22 May 2018 / Published online: 1 June 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Background Gastric cancer (GC) is the second most common leading cause of cancer-related death. Cancer stem cell (CSC)
with the mark of CD44 played an important role in GC. rMETase was wildly exploited as chemotherapeutic option for GC.
Polymers synthetic nanoparticle drug delivery systems have been commonly used for cancer therapy. With the decorating
of Hyaluronic acid (HA), a receptor of CD44, nanoparticles exhibit with good biocompatibility and aqueous solubility.
Methods The characteristic of nanoparticles (NPs) was analyzed by TEM and DLS. The viability and proliferation of GC
cells were examined by MTT assays. The levels of CD44, Cyt C, and c-caspase 3 were examined by Western blot. The level
of ROS was measured by DCFH-DA assays. The morphology of tissues was detected using hematoxylin–eosin (H&E) stain.
Nude mice xenograft models were used to evaluate the eﬀect of HA-PAMAM-Au-METase on GC.
Results The transfection of rMETase carried by HA-G5 PAMAM-Au visibly inhibited the proliferation and tumorsphere
formation of GC cells through obviously enhancing METase activity. Elevation of METase activity suppressed the prolifera-
tion of CD44(+) GC cells through down-regulating MET in cellular supernatant that resulted in the increase of Cyc C and
ROS levels. The number of CD44(+) GC cells in nude mice injected with G5 PAMAM-Au-METase decorated by HA was
markly declined resulting in the inhibition of tumor growth.
Conclusion HA-G5 PAMAM-Au-METase signiﬁcantly suppressed tumor growth of GC by targeted damaging the mito-
chondrial function of CD44(+) gastric CSCs.
Keywords HA-PAMAM-Au-METase · CD44 · Gastric cancer stem cells
With a high incidence in the word, gastric cancer (GC) is the
second most common leading cause of cancer-related death
(Xu et al. 2014; Shah and Kelsen 2010). Although the devel-
opment of therapy for cancers has enhanced the survival
of patients with GC, a larger numbers of GC patients were
diagnosed with the advanced or metastatic gastric cancer
(Lee et al. 2012). Among these patients with advanced or
metastatic gastric cancer, over 50% exhibited the response
to multi-agent chemotherapy. However, the majority of them
presented the chemotherapy resistance with the prolonga-
tion of therapy time (Bölke et al. 2008). As the cancers har-
bor with the capacity for self-renewal and diﬀerentiating
into many cell types (Rocco et al. 2012), the cancer stem
cell (CSC) was proved to be more resistant to chemother-
apy than non-CSCs (Alison et al. 2012). Moreover, it was
demonstrated that CD44 was a marker of CSC involved in
tumorsphere formation in vitro and tumor formation in vivo
(Takaishi et al. 2009).
With the advance in gene therapies, mounting genes were
found to be a key role in treating cancer. For instances, the
p53 gene has been revealed to suppress the growth of cancer
cells and promote apoptosis (Harris 1996). The HSV-TK
Yi-Fan Li and Hou-Ting Zhang have contributed equally to this
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0043 2-018-2678-5) contains
supplementary material, which is available to authorized users.
* Lin Xin
Department of General Surgery, The Second Aﬃliated
Hospital of Nanchang University, NO. 1 Minde Rd,
Nanchang 330006, People’s Republic of China