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Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs
- Huang, Lei, Tao, Kaixiong, Liu, Jia, Qi, Chao, Xu, Luming, Chang, Panpan, Gao, Jinbo, Shuai, Xiaoming, Wang, Guobin, Wang, Zheng, Wang, Lin
- ACS Applied Materials & Interfaces 2016 v.8 no.10 pp. 6577-6585
- adverse effects, biocompatibility, chemical bonding, cytotoxicity, doxorubicin, drug therapy, folate receptors, folic acid, hydrophilicity, hydrophobicity, immune response, lysosomes, nanoparticles, neoplasm cells, neoplasms, pH, sericin, silk
- 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.