title: Reversion of pH-induced physiological drug resistance: a novel function of copolymeric nanoparticles.
abstract: OBJECTIVE
  The extracellular pH of cancer cells is lower than the intracellular pH. Weakly basic anticancer drugs will be protonated extracellularly and display a decreased intracellular concentration. In this study, we show that copolymeric nanoparticles (NPs) are able to overcome this "pH-induced physiological drug resistance" (PIPDR) by delivering drugs to the cancer cells via endocytosis rather than passive diffussion.
  
  
  METHODS
  As a model nanoparticle, Tetradrine (Tet, Pka 7.80) was incorporated into mPEG-PCL. The effectiveness of free Tet and Tet-NPs were compared at different extracellular pHs (pH values 6.8 and 7.4, respectively) by MTT assay, morphological observation and apoptotic analysis in vitro and on a murine model by tumor volume measurement, PET-CT scanning and side effect evaluation in vivo.
  
  
  RESULTS
  The cytotoxicity of free Tet decreased prominently (P<0.05) when the extracellular pH decreased from 7.4 to 6.8. Meanwhile, the cytotoxicity of Tet-NPs was not significantly influenced by reduced pH. In vivo experiment also revealed that Tet-NPs reversed PIPDR more effectively than other existing methods and with much less side effects.
  
  
  CONCLUSIONS
  The reversion of PIPDR is a new discovered mechanism of copolymeric NPs. This study emphasized the importance of cancer microenvironmental factors in anticancer drug resistance and revealed the superiority of nanoscale drug carrier from a different aspect.
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Rutian
authors.initials: R
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Zhenshu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiqun
authors.initials: X
authors.lastname: Jiang
authors.forename: Lixia
authors.initials: L
authors.lastname: Yu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qian
authors.forename: Wanhua
authors.initials: W
authors.lastname: Guo
authors.forename: Yitao
authors.initials: Y
authors.lastname: Ding
authors.forename: Baorui
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D011091:Polyesters; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); C009438:tetrandrine; D011092:Polyethylene Glycols