title: Pulmonary Codelivery of Doxorubicin and siRNA by pH-Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer.
abstract: A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis-aconitic anhydride (CA, a pH-sensitive linker) to obtain PEI-CA-DOX conjugates. The PEI-CA-DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI-CA-DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI-CA-DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma-bearing mice, the PEI-CA-DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long-term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI-CA-DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, China.
authors.forename: Caina
authors.initials: C
authors.lastname: Xu
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, China.
authors.forename: Jingpeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, China.
authors.forename: Huayu
authors.initials: H
authors.lastname: Tian
authors.affiliation: Departments of Biomedical Engineering and Pharmaceutics, Purdue University, West Lafayette, IN, 47907, USA.
authors.forename: Kinam
authors.initials: K
authors.lastname: Park
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, China.
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000812:Anhydrides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D009929:Organ Size / Q000187:drug effects; D010316:Particle Size; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D055672:Static Electricity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000812:Anhydrides; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D004317:Doxorubicin; D011094:Polyethyleneimine
keywords: anticancer therapy; antitumor effect; codelivery; pH-sensitive; pulmonary delivery