Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA-nanocomplex in a nanoparticle system.
Many cancers fail to respond to immunotherapy as a result of immune suppression by the tumor microenvironment. The exogenous expression of immune cytokines to reprogram the tumor microenvironment represents an approach to circumvent this suppression. The present studies describe the development of a novel dual nanoparticle (DNP) system for driving DNA expression vectors encoding inflammatory cytokines in tumor cells. The DNP system consists of a DNA expression vector-cationic peptide nanocomplex (NC) surrounded by a diblock polymeric NP. Tumor necrosis factor alpha (TNF) was selected as the prototype cytokine for this system, based on its pleotropic inflammatory and anti-cancer activities. Our results demonstrate that the DNP system is highly effective in driving expression of TNF in tumor cells. We also demonstrate that the DNPs are effective in inducing apoptosis and anti-tumor activity. These findings support a novel immunotherapeutic approach for the intratumoral delivery of DNA vectors that express inflammatory cytokines.
Center for Biomedical Engineering, Indian Institute of Technology, Delhi, India.
Vasundhara
V
Shukla
Center for Biomedical Engineering, Indian Institute of Technology, Delhi, India.
Manu
M
Dalela
Institute of Genomics and Integrative Biology, Delhi, India.
Manika
M
Vij
Department of Radiation and Cellular Oncology, University of Chicago Medicine, Chicago, IL, USA.
Ralph
R
Weichselbaum
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Surender
S
Kharbanda
Institute of Genomics and Integrative Biology, Delhi, India.
Munia
M
Ganguli
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: donald_kufe@dfci.harvard.edu.
Donald
D
Kufe
Center for Biomedical Engineering, Indian Institute of Technology, Delhi, India; All India Institute of Medical Science, Delhi, India. Electronic address: harpal2000@yahoo.com.
Harpal
H
Singh
D016207:Cytokines; D004247:DNA; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D004247:DNA
DNA expression vector; Intratumoral delivery; Nanocomplexes; Nanoparticles; Tumor necrosis factor