Persistent Transgene Expression Following Intravenous Administration of a Liposomal Complex: Role of Interleukin-10-Mediated Immune Suppression

Ito, Isao; Saeki, Tomoyuki; Mohuiddin, Imran; Saito, Yuji; Branch, Cynthia D.; Vaporciyan, Ara A.; Roth, Jack A.; Ramesh, Rajagopal

doi:10.1016/j.ymthe.2004.01.007

Cited by 17 publications

(8 citation statements)

References 47 publications

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“…Intravenous treatments with DOTAP:Chol-mda7 nanoparticles resulted in a reduction in the number of experimental lung tumors. Moreover, we observed no resistance to repeated treatments in agreement with our previous studies (Ramesh et al, 2001;Ito et al, 2003Ito et al, , 2004. This study clearly demonstrates for the first time the ability of intravenously delivered DOTAP:Chol-mda-7 nanoparticles to inhibit experimental lung metastasis in both immunodeficient and immunocompetent animals.…”

Section: Discussionsupporting

confidence: 92%

Local and Systemic Inhibition of Lung Tumor Growth After Nanoparticle-Mediated<I> mda-7/IL-24</I> Gene Delivery

Ramesh¹,

Ito²,

Saito³

et al. 2004

dna cell biol

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The human melanoma differentiation associated gene-7 (mda-7), also known as interleukin-24 (IL-24), is a novel gene with tumor suppressor, antiangiogenic, and cytokine properties. In vitro adenovirus-mediated gene transfer of the human mda-7/IL-24 gene (Ad-mda-7) results in ubiquitous growth suppression of human cancer cells with minimal toxicity to normal cells. Intratumoral administration of Ad-mda-7 to lung tumor xenografts results in growth suppression via induction of apoptosis and antiangiogenic mechanisms. Although these results are encouraging, one limitation of this approach is that its locoregional clinical application-systemic delivery of adenoviruses for treatment of disseminated cancer is not feasible at the present time. An alternative approach that is suitable for systemic application is non-viral gene delivery. We recently demonstrated that DOTAP:cholesterol (DOTAP:Chol) nanoparticles effectively deliver tumor suppressor genes to primary and disseminated lung tumors. In the present study, therefore, we evaluated nanoparticle-mediated delivery of the human mda-7/IL-24 gene to primary and disseminated lung tumors in vivo. We demonstrate that DOTAP:Chol efficiently delivers the mda-7/IL-24 gene to human lung tumor xenografts, resulting in suppression of tumor growth. Growth-inhibitory effects were observed in both primary (P ‫؍‬ 0.001) and metastatic lung tumors (P ‫؍‬ 0.02). Furthermore, tumor vascularization was reduced in mda-7/IL-24-treated tumors. Finally, growth was also inhibited in murine syngenic tumors treated with DOTAP:Chol-mda-7 nanoparticles (P ϭ 0.01). This is the first report demonstrating (1) systemic therapeutic effects of mda-7/IL-24 in lung cancer, and (2) antitumor effects of human mda-7 in syngeneic cancer models. Our findings are important for the development of mda-7/IL-24 treatments for primary and disseminated cancers. 850 DOTAP:Chol nanoparticles were synthesized and extruded through Whatman filters (Kent, UK) of decreasing size (1.0, 0.45, 0.2, and 0.1 m) as described elsewhere Templeton et al., 1997). DOTAP:Chol-DNA nanoparticles were prepared fresh 2 to 3 h prior to injection in mice. Particle size analysisFreshly prepared DOTAP:Chol-DNA nanoparticles were analyzed for mean particle size by using the N4 particle size analyzer (Coulter, Miami, FL). The mean particle size of the DOTAP: Chol-DNA nanoparticles ranged between 300 and 325 nm.

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Section: Discussionsupporting

confidence: 92%

Local and Systemic Inhibition of Lung Tumor Growth After Nanoparticle-Mediated<I> mda-7/IL-24</I> Gene Delivery

Ramesh¹,

Ito²,

Saito³

et al. 2004

dna cell biol

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“…The nonspecific antitumor activity observed with the CAT DNA is not surprising and is in agreement with previous reports where nonspecific antitumor activity was demonstrated when treated with control plasmid DNA's complexed to liposomal vectors. 17,[20][21][22][23] The induction of an inflammatory response following injection of liposome-DNA complex has been shown to mediate the nonspecific activity antitumor activity. 20,21 However, the antitumor activity observed in animals treated with wt-FUS1 was significantly higher than in animals treated with CAT demonstrating the specificity.…”

Section: Discussionmentioning

confidence: 99%

Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo

et al. 2004

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Lung cancer is one of the leading causes of death in the world. The underlying cause for lung cancer has been attributed to various factors that include alteration and mutation in the tumor suppressor genes. Restoration of normal function of the tumor suppressor gene is a potential therapeutic strategy. Recent studies have identified a group of candidate tumor suppressor genes on human chromosome 3p21.3 that are frequently deleted in human lung and breast cancers. Among the various genes identified in the 3p21.3 region, we tested the antitumor activity of the FUS1 gene in two human non-small-cell lung cancer (NSCLC) xenografts in vivo. Intratumoral administration of FUS1 gene complexed to DOTAP:cholesterol (DOTAP:Chol) liposome into subcutaneous H1299 and A549 lung tumor xenograft resulted in significant (P ¼ .02) inhibition of tumor growth. Furthermore, intravenous injections of DOTAP:Chol-FUS1 complex into mice bearing experimental A549 lung metastasis demonstrated significant (P ¼ .001) decrease in the number of metastatic tumor nodules. Finally, lung tumor-bearing animals when treated with DOTAP:Chol-FUS1 complex demonstrate prolonged survival (median survival time: 80 days, P ¼ .01) compared to control animals. This result demonstrates the potent tumor suppressive activity of the FUS1 gene and is a promising therapeutic agent for treatment of primary and disseminated human lung cancer.

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“…The differences in the outcomes were due to difference in the animal models used. We demonstrated that mice bearing tumors produced immunosuppressive factors within the tumor microenvironment that altered the host immune pathology resulting in no inhibitory effects on transgene expression [51]. Additionally, nanocarrier tracking studies demonstrated tumors that were larger in size had more nanocarriers compared to tumors that were smaller in size [49].…”

Section: Gene-based Nanotherapymentioning

confidence: 99%

Tumor Suppressor Gene-Based Nanotherapy: From Test Tube to the Clinic

Shanker

Jin

Branch

et al. 2011

Journal of Drug Delivery

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Cancer is a major health problem in the world. Advances made in cancer therapy have improved the survival of patients in certain types of cancer. However, the overall five-year survival has not significantly improved in the majority of cancer types. Major challenges encountered in having effective cancer therapy are development of drug resistance by the tumor cells, nonspecific cytotoxicity, and inability to affect metastatic tumors by the chemodrugs. Overcoming these challenges requires development and testing of novel therapies. One attractive cancer therapeutic approach is cancer gene therapy. Several laboratories including the authors' laboratory have been investigating nonviral formulations for delivering therapeutic genes as a mode for effective cancer therapy. In this paper the authors will summarize their experience in the development and testing of a cationic lipid-based nanocarrier formulation and the results from their preclinical studies leading to a Phase I clinical trial for nonsmall cell lung cancer. Their nanocarrier formulation containing therapeutic genes such as tumor suppressor genes when administered intravenously effectively controls metastatic tumor growth. Additional Phase I clinical trials based on the results of their nanocarrier formulation have been initiated or proposed for treatment of cancer of the breast, ovary, pancreas, and metastatic melanoma, and will be discussed.

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Persistent Transgene Expression Following Intravenous Administration of a Liposomal Complex: Role of Interleukin-10-Mediated Immune Suppression

Cited by 17 publications

References 47 publications

Local and Systemic Inhibition of Lung Tumor Growth After Nanoparticle-Mediated<I> mda-7/IL-24</I> Gene Delivery

Local and Systemic Inhibition of Lung Tumor Growth After Nanoparticle-Mediated<I> mda-7/IL-24</I> Gene Delivery

Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo

Tumor Suppressor Gene-Based Nanotherapy: From Test Tube to the Clinic

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