Enzyme and Reactive Oxygen Species–Responsive Dual-Drug Delivery Nanocomplex for Tumor Chemo-Photodynamic Therapy

Qian Xie,1,* Shi Gao,1,* Rui Tian,2 Guohao Wang,3,4 Zainen Qin,5 Minglong Chen,1 Wenhui Zhang,1 Qiang Wen,1 Qingjie Ma,1 Lei Zhu1 1Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130033, People’s Republic of China; 2Department of Ophthalmology Second Hospital, Jilin University, Changchun, 130033, People’s Republic of China; 3Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 4Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 5Department of Oral Radiology, Guangxi Medical University College of Stomatology, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingjie Ma; Lei Zhu, Email maqj@jlu.edu.cn; zeh.ray8@gmail.comIntroduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy.Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5β-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy.Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model.Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.Keywords: chemotherapy, photodynamic therapy, hyaluronic acid, responsive nanoparticle, drug delivery