title: Low-molecular-weight protamine-modified PLGA nanoparticles for overcoming drug-resistant breast cancer.
abstract: Multidrug resistance (MDR) is a major challenge for cancer therapy. Herein, we report a simple yet effective system, cell-penetrating peptide (CPP)-assisted poly(lactic-co-glycolic acid nanoparticles (PLGA NPs), for improving doxorubicin (DOX) delivery and overcoming MDR cancer. We selected the naturally derived CPP low-molecular-weight protamine (LMWP) to modify PLGA NP for enhanced drug delivery. We demonstrated that multiple mechanisms ("synergistic multipronged delivery") were responsible for the anti-MDR effects of LMWP/PLGA NP. This delivery system could boost intracellular and intranuclear delivery, thereby circumventing drug efflux. Use of a P-glycoprotein inhibitor did not further increase the efficiency of intracellular delivery of LMWP/PLGA/DOX NP, suggesting that delivery of LMWP-based NP was not affected by transporter-mediated drug efflux. Importantly, enhanced uptake and penetration within the tumor was found in mice given LMWP-based NP. LMWP/PLGA NP effectively arrested tumor growth in mice harboring drug-resistant breast tumors, thereby improving treatment outcomes without detectable toxicities. These data suggest that our system could provide effective yet safe anti-MDR cancer therapy based on a synergistic, multipronged drug-delivery strategy.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China; Zhengzhou University College of Pharmaceutical Sciences, 100 Science Road, Zhengzhou 450001, China.
authors.forename: Huixin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Zhengzhou University College of Pharmaceutical Sciences, 100 Science Road, Zhengzhou 450001, China.
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Tianjin University School of Chemical Engineering and Technology, Tianjin 300072, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Gong
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Huining
authors.initials: H
authors.lastname: He
authors.affiliation: University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109-1065, USA.
authors.forename: Meong Cheol
authors.initials: MC
authors.lastname: Shin
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109-1065, USA. Electronic address: vcyang@umich.edu.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Hai-ke Road, Shanghai 201203, China. Electronic address: yzhuang@simm.ac.cn.
authors.forename: Yongzhuo
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011479:Protamines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011479:Protamines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin
keywords: Breast cancer; Cell-penetrating peptide; Doxorubicin; Low-molecular-weight protamine; Multidrug resistance; PLGA nanoparticle