title: Imaging the cytosolic drug delivery mechanism of HDL-like nanoparticles.
abstract: OBJECTIVE
  Molecular therapeutics often require an effective nanoparticle-based delivery strategy to transport them to cytosolic organelles to be functional. Recently, a cytosolic delivery strategy based on the scavenger receptor class B type I (SR-BI) mediated pathway has shown great potential for the effective delivery of theranostics agents into the cytoplasm of cells without detrimental endosomal entrapment. This study elucidates this unique delivery mechanism for improving cytosolic drug delivery.
  
  
  METHODS
  Multifluorophore-labeled HDL-mimicking peptide phospholipid scaffold (HPPS) nanoparticles were developed. Fluorescence imaging was utilized to examine HPPS transporting payloads into cells step by step through sequential inhibition studies.
  
  
  RESULTS
  HPPS specifically recognizes and binds to SR-BI, then interacts with SR-BI, which results in direct transport of payload molecules into the cell cytoplasm without entire particles internalization. The cytosolic transport of payloads occurred through a temperature- and energy-independent pathway, and was also different from actin- and clathrin-mediated endocytosis. Furthermore, this transport was significantly inhibited by disruption of lipid rafts using filipin or methyl-β-cyclodextrin.
  
  
  CONCLUSIONS
  The cytosolic delivery of payloads by HPPS via SR-BI targeting is predominately mediated through a lipid rafts/caveolae-like pathway. This cytosolic delivery strategy can be utilized for transporting molecular therapeutics that require their action sites to be within cytosolic organelles to enhance therapeutic effect.
authors.affiliation: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics Huazhong University of Science & Technology, Wuhan, 430074, China.
authors.forename: Qiaoya
authors.initials: Q
authors.lastname: Lin
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Ng
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cao
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000199:Actins / Q000494:pharmacology; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism* / Q000648:ultrastructure; D016503:Drug Delivery Systems; D005372:Filipin / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000493:pharmacokinetics*; D021962:Membrane Microdomains; D053758:Nanoparticles / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000199:Actins; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D010743:Phospholipids; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D005372:Filipin