title: Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance.
abstract: Resistance to treatment with anticancer drugs is a signiï¬cant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efï¬cacy in vitro and in the drug-resistant MCF-7/Adr (DOX) xenograft tumor model. More specifically, the nanoparticles signiï¬cantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.|The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center of Breast Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Henghui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Otorhinolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Fengjiao
authors.initials: F
authors.lastname: Yan
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Mingna
authors.initials: M
authors.lastname: Sun
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Lingran
authors.initials: L
authors.lastname: Du
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Feng
authors.affiliation: The College of Pharmaceutics Science, Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles; D020442:Poloxamer / Q000737:chemistry*; D043862:Rotaxanes / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D003505:Cyclodextrins; D004337:Drug Carriers; D043862:Rotaxanes; C475673:polyrotaxane; D020442:Poloxamer; D004317:Doxorubicin; D005492:Folic Acid