CXCR4-Targeted and Redox Responsive Dextrin Nanogel for Metastatic Breast Cancer Therapy

• Published in: Biomacromolecules 2017-06, Vol.18 (6), p.1793-1802
• Main Authors: Zhang, Feiran, Gong, Siman, Wu, Jun, Li, Huipeng, Oupicky, David, Sun, Minjie
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemokine CXCL12 - antagonists & inhibitors; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Dextrins - chemistry; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Carriers; Female; Gels; Gene Expression; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Nanostructures - administration & dosage; Nanostructures - chemistry; Nanostructures - ultrastructure; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oxidation-Reduction; Protein Binding; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.7b00208

The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis.