Efficient inhibition of ovarian cancer by recombinant CXC chemokine ligand 10 delivered by novel biodegradable cationic heparin-polyethyleneimine nanogels

Abstract

Abstract. Currently, great interest is focused on the antineoplastic effects of CXC chemokine ligand 10 (IP-10/CXCL10). IP-10 has shown significant antitumor and anti-metastatic properties via immunological, antiangiogenic and anti-neoplastic mechanisms. However, very few studies on the antitumor activity of IP-10 in human ovarian cancer have been reported. The use of polymeric nanoparticles to deliver functional genes intraperitoneally holds much promise as an effective therapy for ovarian cancer. In our study, a recombinant plasmid expressing IP-10 (pVITRO-IP-10) was constructed, and biodegradable cationic heparin-polyethyleneimine (HPEI) nanogels were prepared to deliver pVITRO-IP-10 into SKOV3 human ovarian cancer cells. Transfection efficiency was detected by expression profiling of green fluorescent protein. The expression of IP-10 was determined using RT-PCR and western blot analysis. In vitro, cell proliferation was evaluated by MTT assay. Apoptosis was examined by Hoechst33258/PI staining and flow cytometry assays. The effect on the inhibition of angiogenesis was evaluated by tube formation assay using human umbilical vein endothelial cells (HUVECs). Moreover, a SKOV3 intraperitoneal ovarian carcinomatosis model was established to investigate the antitumor activity of HPEI+pVITRO-IP-10 complexes in nude mice. Tumor weights were evaluated during the treatment course. Cell proliferation and apoptosis were evaluated by Ki-67 immunochemical staining and TUNEL assay, and the antiangiogenic effect of pVITRO-IP-10 was assessed by CD31 immunochemical staining and alginate-encapsulated tumor cell assay. pVITRO-IP-10 was efficiently transfected into SKOV3 cells by HPEI nanogels. Intraperitoneal administration of HPEI+pVITRO-IP-10 complexes led to effective growth inhibition of ovarian cancer, in which tumor weight decreased by ~69.92% in the treatment group compared with that in the empty vector control group. Meanwhile, decreased cell proliferation, increased tumor cell apoptosis and reduction in angiogenesis were observed in the HPEI+pVITRO-IP-10 group compared with those in the control groups. These results indicated that HPEI nanogel delivery of pVITRO-IP-10 may be of value in the treatment against human ovarian cancer.

Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene

“…15 In our previous study, the biodegradable cationic HPEI nanoparticles have been proved to be capable of delivering the gene into cells effectively and safely, 16,17 demonstrating high potential in gene delivery.…”

Identification of novel dipeptidyl peptidase 9 substrates by two‐dimensional differential in‐gel electrophoresis

“…Our data now establish CXCL10 as a DPP9 substrate in vitro . Similarly, S100‐A10, SET and NUCB1 are mediators of immunity and/or inflammatory response . The potential of DPPs to modify and potentially alter the function of these proteins may therefore prove to be important in the regulation of immune responses in vivo .…”

Antitumor Effect of IP-10 by Using Two Different Approaches: Live Delivery System and Gene Therapy

“…In the present study, 10 kDa interferon γ-induced protein (IP-10), a CXC chemokine, was used as an immunotherapeutic agent. This chemokine induces antitumor and antimetastatic activities in different ways including immunological and antiangiogenic mechanisms [ 12 ]. We used the murine estrogen-nonresponsive mammary carcinoma cells, named 4T1 cells, which multiply rapidly and cause metastatic tumors in BALB/c mice [ 13 ].…”