title: Enhanced chemotherapy of cancer using pH-sensitive mesoporous silica nanoparticles to antagonize P-glycoprotein-mediated drug resistance.
abstract: Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSN-Hydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo.
authors.affiliation: Division of Medical Engineering Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
authors.forename: I-Ping
authors.initials: IP
authors.lastname: Huang
authors.forename: Shu-Pin
authors.initials: SP
authors.lastname: Sun
authors.forename: Shih-Hsun
authors.initials: SH
authors.lastname: Cheng
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Chia-Yan
authors.initials: CY
authors.lastname: Wu
authors.forename: Chung-Shi
authors.initials: CS
authors.lastname: Yang
authors.forename: Leu-Wei
authors.initials: LW
authors.lastname: Lo
authors.forename: Yiu-Kay
authors.initials: YK
authors.lastname: Lai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D012822:Silicon Dioxide / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006835:Hydrazones; D012822:Silicon Dioxide; D004317:Doxorubicin