title: Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs.
abstract: The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo-cytotoxicity. Together, this study suggests that these FA-SND nanoparticles may be a potentially effective carrier particularly useful for delivering hydrophobic chemotherapeutic agents for treating cancers with high-level expression of folate receptors.
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Lei
authors: L
authors: Huang
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Kaixiong
authors: K
authors: Tao
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Jia
authors: J
authors: Liu
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Chao
authors: C
authors: Qi
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Luming
authors: L
authors: Xu
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Panpan
authors: P
authors: Chang
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Jinbo
authors: J
authors: Gao
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Xiaoming
authors: X
authors: Shuai
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Guobin
authors: G
authors: Wang
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Zheng
authors: Z
authors: Wang
authors: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, §Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, ⊥Medical Research Center, Union Hospital, Tongji Medical College, ∥Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors: Lin
authors: L
authors: Wang
mesh_terms: D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047030:Sericins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047030:Sericins; D004317:Doxorubicin
keywords: doxorubicin; folate; nanoparticles; pH sensitivity; sericin