title: Polymeric Nanomedicine for Combined Gene/Chemotherapy Elicits Enhanced Tumor Suppression.
abstract: Combination treatment through simultaneous delivery of DNA and anticancer drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employed a combination therapy for eliminating both the tumor cells and intratumoral neovascular network based on the nanoplatform we designed. Pigment epithelium-derived factor (PEDF) gene, a powerful antiangiogenic agent, and the clinically widely used chemotherapy agent paclitaxel (PTX) were simultaneously encapsulated in the same nanoparticle by a modified double-emulsion solvent evaporation method. The dual-drug-loaded nanoparticles (D/P-NPs) exhibited a uniform spherical morphology and released PTX and PEDF gene in a sustained manner. D/P-NPs showed an enhanced antitumor effect on C26 and A549 cells and a stronger inhibitory activity on proliferation of HUVECs. Moreover, D/P-NPs could dramatically elevate the PEDF expression levels in both C26 and A549 cells in comparison with PEDF gene loaded nanoparticles and significantly promote the cellular uptake of PTX. Additionally, microtubules were stabilized and G2/M phase arrest along with a higher subG1 cell population was induced by D/P-NPs in contrast to PTX or PTX loaded nanoparticles. Besides, D/P-NPs showed sustained release of PTX and PEDF gene in tumors as well as long-term gene expression. A significantly improved anticancer effect was also demonstrated in a C26 subcutaneous tumor model using this combinational therapy. D/P-NPs could sharply reduce the microvessel density and significantly promoted tumor cell apoptosis in vivo. More importantly, the in vivo distribution, serological and biochemical analysis, and H&E staining revealed that D/P-NPs had no obvious toxicity. Our study suggested that this novel polymeric nanomedicine had great potential for improving the therapeutic efficacy of combined gene/chemotherapy of cancer.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.|Central Laboratory, Science Education Department, Chengdu Normal University , Chengdu, Sichuan 610041, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Fazhan
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yu
authors.affiliation: College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities , Chengdu, Sichuan 610041, China.
authors.forename: Lili
authors.initials: L
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Shuangzhi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology/Collaborative Innovation Center of Biotherapy, Medical School of Nankai University , Tianjin 300071, China.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu, Sichuan 610041, China.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Song
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D005136:Eye Proteins / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009414:Nerve Growth Factors / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005136:Eye Proteins; D009414:Nerve Growth Factors; D017239:Paclitaxel; D011108:Polymers; D012333:RNA, Messenger; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: PLGA nanoparticles; codelivery; combination therapy; paclitaxel; pigment epithelium-derived factor