title: A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy.
abstract: Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy. However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8+cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson-Crick base pairing would further enhance CD8+cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo. This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo. Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN and antigens.
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Duan
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Feng
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Wentong
authors.initials: W
authors.lastname: Sun
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Liu
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Ge
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China. Electronic address: zhenhuali1013@163.com.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China. Electronic address: jczhang6970@163.com.
authors.forename: Jinchao
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis*; D004357:Drug Synergism; D006863:Hydrogen-Ion Concentration; D000073396:Metal-Organic Frameworks / Q000008:administration & dosage / Q000138:chemical synthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D010316:Particle Size; D000067996:RAW 264.7 Cells
chemical_list: D000951:Antigens, Neoplasm; D003692:Delayed-Action Preparations; D000073396:Metal-Organic Frameworks; D053769:Nanocapsules
keywords: Co-delivery; Cross-presentation; Immunotherapy; Metal-organic frameworks; pH-responsive