Open AccessA Tumor Vascular‐Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia
Author(s) -
Luan Xin,
Guan YingYun,
Liu HaiJun,
Lu Qin,
Zhao Mei,
Sun Duxin,
Lovell Jonathan F.,
Sun Peng,
Chen HongZhuan,
Fang Chao
Publication year - 2018
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201800034
Subject(s) - hypoxia (environmental) , downregulation and upregulation , prodrug , cancer research , tumor hypoxia , photosensitizer , photodynamic therapy , chemistry , in vivo , pharmacology , medicine , biology , oxygen , biochemistry , microbiology and biotechnology , organic chemistry , gene , radiation therapy
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.