Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin

Abstract

NK4, composed of the NH 2 -terminal hairpin and subsequent four-kringle domains of hepatocyte growth factor (HGF), acts as an HGF-antagonist and angiogenesis inhibitor. This study is an investigation to evaluate the feasibility of controlled release formulation of NK4 plasmid DNA in suppressing the tumor growth, and lung metastasis. Biodegradable cationized gelatin microspheres were prepared for the controlled release of an NK4 plasmid DNA. The cationized gelatin microspheres incorporating NK4 plasmid DNA could continuously release plasmid DNA over 28 days as a result of microspheres degradation following the subcutaneous injection. The injection of cationized gelatin microspheres incorporating NK4 plasmid DNA into the subcutaneous tissue significantly prolonged the survival time period of the mice bearing Lewis lung carcinoma tumor. Increases in the tumor volume and the number of lung metastatic nodules of NK4 plasmid DNA release group were suppressed to a significantly greater extent than that of solution-injected group (77.4 and 64.0%, respectively). The number of blood vessels and the apoptosis cells in the tumor tissue were significantly suppressed (80.4%) and increased (127.3%) against free NK4 plasmid DNA-injected group. Thus, the controlled release of NK4 plasmid DNA augmented angiogenesis suppression and apoptosis of tumor cells, which resulted in suppressed tumor growth. We conclude that this controlled release technology is promising to enhance the tumor suppression achieved by gene expression of NK4.

RETRACTED ARTICLE: Enhanced suppression of tumor growth using a combination of NK4 plasmid DNA-PEG engrafted cationized dextran complex and ultrasound irradiation

“…Our previuos study revealed that the injection of cationized gelatin microspheres incorporating NK4 plasmid DNA significantly inhibited angiogenesis in tumor tissue while increased the number of apoptotic tumor cells. 53 These findings are consistent with previous studies in which angiogenesis inhibitors suppressed the tumor growth through increasing apoptosis of tumor cells. 54,55 Thus, it is possible that NK4 suppresses primary tumor growth mainly through inhibition of tumor angiogenesis.…”

Nanoparticle delivery of anti-metastatic NM23-H1 gene improves chemotherapy in a mouse tumor model

“…2,3 In spite of their high transduction efficiency, viral vectors are associated with immunogenicity, toxicity and possible mutagenesis of the target cells. 4 Non-viral vectors have become an attractive alternative, [5][6][7] but the low efficiency of transfection results in less efficient targeting of genes to the tissue of interest. The lack of an effective and safe gene targeting vector has become the major barrier to the wide application of gene therapy.…”

Controlled Delivery of T-box21 Small Interfering RNA Ameliorates Autoimmune Alopecia (Alopecia Areata) in a C3H/HeJ Mouse Model

“…8 An aqueous solution of 10 wt % cationized gelatin (10 ml) was preheated at 40°C and then added dropwise into 375 ml of olive oil preheated at 40°C, while an impeller stirring at 420 rpm was used for 10 minutes to yield a water-in-oil emulsion. The emulsion temperature was decreased to 4°C followed by further stirring for 30 minutes for the natural gelation of gelatin aqueous solution.…”

“…The carboxyl groups of gelatin were chemically converted by introducing amino groups for cationization of gelatin. 8 Briefly, ethylenediamine and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt were added to 250 ml of 100 mmol/L PBS containing 5 g of gelatin. The molar ratio of ethylenediamine to the carboxyl groups of gelatin was 50.…”

“…5 Gene therapy using siRNA in vivo has been exploited successfully in several mouse disease models; intravenous injections of siRNA limited the rate of metastasis of prostate cancer, 6 and intralesional injections of siRNA decreased the incidence of herpes simplex virus infection. 7 Here we introduced another siRNA drug delivery system using cationized gelatin 8 as a new therapeutic approach, targeting Tbox21 gene (Tbx21) to repress the expression of interferon-␥ gene (Ifng). Tbx21 gene was formerly known as T-bet gene and plays an important role in control of the Ifng gene expression and Th1 cell differentiation and function.…”