Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy.
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.
Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, Jiangsu 210009, China.
Yazhe
Y
Wang
Ying
Y
Xie
Jing
J
Li
Zheng-Hong
0000-0001-9783-5108
ZH
Peng
Yuri
Y
Sheinin
Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, Jiangsu 210009, China.
Jianping
J
Zhou
Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, Jiangsu 210009, China.
David
0000-0003-4710-861X
D
Oupický
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D000860:Hypoxia / Q000188:drug therapy*; D007208:Indocyanine Green / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D051379:Mice; D015394:Molecular Structure; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D000077704:Tirapazamine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species; D000077704:Tirapazamine; D007208:Indocyanine Green
cancer; hypoxia; iRGD; nanoparticles; photodynamic therapy; tumor penetration