title: Actively targeting D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) nanoparticles as vesicles for chemo-photodynamic combination therapy of doxorubicin-resistant breast cancer.
abstract: Drug resistance is the major reason for therapeutic failure during cancer treatment. Chemo-photodynamic combination therapy has potential to improve the treatment efficiency in drug-resistant cancers, but is limited by the incompatible physical properties of the photosensitizer with a chemo-drug and poor accumulation of both drugs into the inner areas of the tumor. Herein, a novel drug delivery system was designed by incorporating the photosensitizer, chlorine 6, chemically in the shell and the chemo-drug, doxorubicin, physically in the core of D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) nanoparticles with a targeting ligand, tLyp-1 peptide, decorated over the surface (tLyp-1-NP). This nanoparticle with a high drug loading capacity of both the photosensitizer and chemo-drug is expected to realize chemo-photodynamic combination therapy of drug-resistant cancer and simultaneously achieve the specific deep penetration and accumulation of drugs into the inner areas of tumor. tLyp-1-NP was prepared via a nanoprecipitation method and it exhibited a uniformly spherical morphology with a size of approximately 130 nm. After appropriate irradiation, tLyp-1-NP showed high cellular uptake and strong cytotoxicity in both human umbilical vein endothelial cells (HUVEC cells) and doxorubicin-resistant human breast adenocarcinoma cells (MCF-7/ADR cells) in vitro. After intravenous administration, compared with the unmodified NPs, tLyp-1-NP was found to have superior tumor targeting ability and more potent reversion of doxorubicin-resistant cancer. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and the hematoxylin and eosin staining of the treated tumors further demonstrated the anti-tumor efficacy of tLyp-1-NP in the presence of a laser. These observations collectively suggest the potential of tLyp-1-NP for the actively targeting chemo-photodynamic combination therapy of drug-resistant cancer.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, PR China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Xingye
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Yao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Mengshi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. chenjun@fudan.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry*; D011166:Porphyrins / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013386:Succinates / Q000737:chemistry*; D014183:Transplantation, Heterologous
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; C533969:LyP-1 peptide; D008823:Micelles; D010456:Peptides, Cyclic; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D013386:Succinates; C000589126:clorin-e(6) trimethyl ester; C514223:poly(lactide)-tocopheryl polyethylene glycol succinate; D011092:Polyethylene Glycols; D004317:Doxorubicin