Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy

• Published in: ACS nano 2017-02, Vol.11 (2), p.2227-2238
• Main Authors: Wang, Yazhe, Xie, Ying, Li, Jing, Peng, Zheng-Hong, Sheinin, Yuri, Zhou, Jianping, Oupický, David
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Proliferation - drug effects; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs; Hypoxia - drug therapy; Indocyanine Green - administration & dosage; Indocyanine Green - chemistry; Indocyanine Green - pharmacology; Injections, Intravenous; Mice; Molecular Structure; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Penetration; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - administration & dosage; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Prodrugs - administration & dosage; Prodrugs - chemistry; Prodrugs - pharmacology; Reactive Oxygen Species - analysis; Reactive Oxygen Species - metabolism; Therapy; Tirapazamine - administration & dosage; Tirapazamine - chemistry; Tirapazamine - pharmacology; Tissue Distribution; Tumor Cells, Cultured; Tumors
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.6b08731

Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy.