A Double-Chamber “Dandelion” Appearance Sequential Drug Delivery System for Synergistic Treatment of Malignant Tumors

Jian Li,1– 3 Qing Zhang,1– 3 Jiahui Cai,1– 3 Yibo Yang,1– 3 Jia Zhang,1– 3 Yanting Gao,1– 3 Shihe Liu,1– 3 Kun Li,1– 3 Ming Shi,1– 3 Zhiwei Liu,1– 3 Liming Gao4 1College of Environmental & Chemical Engineering, Yanshan University, Qinhuangdao, People’s Republic of China; 2Applied Chemistry Key Laboratory of Hebei Province, Yanshan University, Qinhuangdao, People’s Republic of China; 3Key Laboratory of Nanobiotechnology of Hebei Province, Yanshan University, Qinhuangdao, People’s Republic of China; 4Oncology Department, the First Hospital of Qinhuangdao, Qinhuangdao, People’s Republic of ChinaCorrespondence: Jian Li, College of Environment & Chemical Engineering, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, People’s Republic of China, Tel +86-335-8061569, Fax +86-335-8061569, Email Lijianbio@ysu.edu.cnIntroduction: During the combined treatment of tumors, the non-interfering transportation of drugs with different solubilities and the controllable sequential release are the main challenges. Here, we reported a double-chamber “Dandelion” -like sequential drug delivery system to realize the sequential release of different drugs for treating malignant tumors synergistically.Methods: After synthesizing mesoporous silica nanoparticles (MSN) by template method, a hydrophilic chemotherapy drug doxorubicin (DOX) was loaded into the channels of mesoporous silica (MSN) and locked with polydopamine (PDA) coating. Next, β-cyclodextrin (β-CDs) was decorated on PDA by Michael addition reaction, and the hydrophobic photosensitizer chlorin e6 (Ce6) was encapsulated into the hydrophobic chambers of β-CDs. Finally, AS1411 was modified on the surface of PDA and obtained DOX@MSN@PDA-β-CD/Ce6-AS1411 nanoparticles (DMPCCA) through which orthogonal loading and effective controlled release of different drugs were realized.Results: Under the sequential irradiations of 808 nm and 660 nm near-infrared (NIR) laser, PDA promoted the extensive release of Ce6 firstly while playing the effect of photothermal therapy (PTT), further to achieve the effect of photodynamic therapy (PDT) of Ce6. Meanwhile, the rapid release of DOX loaded in MSN channels showed a time lag of about 5 h after Ce6 release, through which it maximized the chemotherapeutic effect. Besides, the present drug loading nano-platform combined passive tumor-targeting effect given by EPR and active tumor-targeting effect endowed by AS1411 realized PTT-PDT-chemotherapy triple mode synergistic combination.Conclusion: We offer a general solution to address the key limitations for the delivery and sequential release of different drugs with different solubilities.Graphical Abstract: Keywords: sequential release, mesoporous silica, chemotherapy, tumor-targeting, PTT-PDT-chemotherapy combination