A Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

• Published in: Advanced science Vol. 5; no. 8; pp. 1800034 - n/a
• Main Authors: Luan, Xin, Guan, Ying‐Yun, Liu, Hai‐Jun, Lu, Qin, Zhao, Mei, Sun, Duxin, Lovell, Jonathan F., Sun, Peng, Chen, Hong‐Zhuan, Fang, Chao
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.08.2018; John Wiley and Sons Inc
• Subjects: Cancer therapies; Chemotherapy; Enzymes; Graphene; graphene oxide; Hypoxia; hypoxia‐activated prodrug; Kinases; Ligands; Nanoparticles; Peptides; photodynamic therapy; Polyethylene glycol; Prostate cancer; Statistical analysis; trimodal therapy; tumor hypoxia; Tumors; Canada; United States > US; trimodal therapy; tumor hypoxia; graphene oxide; hypoxia‐activated prodrug; photodynamic therapy
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.201800034

Vascular‐targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)‐based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of banoxantrone dihydrochloride (AQ4N) (2), a hypoxia‐activated prodrug (HAP), and HIF‐1α siRNA (siHIF‐1α) (3) is reported. The VTP‐induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxia‐induced HIF‐1α acts as a “hidden brake,” through downregulating CYP450 (the dominant HAP‐activating reductases), to substantially hinder AQ4N activation. siHIF‐1α is rationally adopted to suppress the HIF‐1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PC‐3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIF‐1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAP‐activating reductases (CYP450), and this can be well overcome by GO nanoparticle‐mediated siHIF‐1α intervention. Vascular‐targeted photodynamic therapy (VTP) is integrated with hypoxia‐activated prodrug (AQ4N) and HIF‐1α siRNA (siHIF‐1α) for interlocking trimodal therapy. The VTP‐induced aggravated hypoxia is exploited for efficient AQ4N activation for chemotherapy. HIF‐1α induced by hypoxia acts as a “hidden brake,” through downregulating CYP450 reductases, to hinder AQ4N activation. siHIF‐1α is rationally adopted to suppress HIF‐1α expression upon VTP to enhance AQ4N activation.