Biodegradable CpG DNA hydrogels for sustained delivery of doxorubicin and immunostimulatory signals in tumor-bearing mice

• Published in: Biomaterials Vol. 32; no. 2; pp. 488 - 494
• Main Authors: Nishikawa, Makiya, Mizuno, Yumiko, Mohri, Kohta, Matsuoka, Nao, Rattanakiat, Sakulrat, Takahashi, Yuki, Funabashi, Hisakage, Luo, Dan, Takakura, Yoshinobu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2011
• Subjects: adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Advanced Basic Science; amino acid motifs; Animals; biodegradability; Cell Line; Cell Line, Tumor; coculture; Controlled drug release; cytotoxicity; Dentistry; Dinucleoside Phosphates - chemistry; Dinucleoside Phosphates - immunology; DNA; DNA - chemistry; DNA - immunology; doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Drug Carriers - administration & dosage; Drug Carriers - chemistry; Drug delivery; hydrocolloids; Hydrogel; Hydrogels - administration & dosage; Hydrogels - chemistry; Immunization; Immunostimulation; immunostimulation (physiological); luciferase; Luciferases, Firefly - metabolism; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Microscopy, Electron, Scanning; necrosis; oligodeoxyribonucleotides; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; Drug delivery; Immunostimulation; Controlled drug release; Hydrogel; DNA
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2010.09.013

Immunostimulatory CpG DNA was self-assembled to form DNA hydrogels for use as a sustained delivery system for both intercalated doxorubicin (DXR) and immunostimulatory CpG motifs for cancer treatment. X-shaped DNA (X-DNA) was designed as a building unit, and underwent ligation to form DNA hydrogels. Two types of X-DNA were constructed using four oligodeoxynucleotides each, one containing six potent CpG motifs (CpG X-DNA) and the other with none (CpG-free X-DNA). CpG X-DNA was more effective than its components or the CpG-free counterpart in terms of the production of tumor necrosis factor-α from murine macrophage-like RAW264.7 cells, as well as maturation of the murine dendritic DC2.4 cells. The cytotoxic effects of X-DNA, DXR and their complexes were examined in a co-culture system of colon26/Luc cells, a murine adenocarcinoma clone stably expressing firefly luciferase, and RAW264.7 cells. DXR/CpG X-DNA showed the highest ability to inhibit the proliferation of colon26/Luc cells. DXR was slowly released from CpG DNA hydrogels. Injections of DXR/CpG DNA hydrogels into a subcutaneous colon26 tumor effectively inhibited tumor growth. These results show that CpG DNA hydrogels are an effective sustained system for delivery of immunostimulatory signals to TLR9-positive immune cells and DXR to cancer cells.