title: Peripherally cross-linking the shell of core-shell polymer micelles decreases premature release of physically loaded combretastatin A4 in whole blood and increases its mean residence time and subsequent potency against primary murine breast tumors after IV administration.
abstract: OBJECTIVE
  Determine the feasibility and potential benefit of peripherally cross-linking the shell of core-shell polymer micelles on the premature release of physically loaded hydrophobic drug in whole blood and subsequent potency against solid tumors.
  
  
  METHODS
  Individual Pluronic F127 polymer micelles (F127 PM) peripherally cross-linked with ethylenediamine at 76% of total PEO blocks (X-F127 PM) were physically loaded with combretastatin A4 (CA4) by the solid dispersion method and compared to CA4 physically loaded in uncross-linked F127 PM, CA4 in DMSO in vitro, or water-soluble CA4 phosphate (CA4P) in vivo.
  
  
  RESULTS
  X-F127 PM had similar CA4 loading and aqueous solubility as F127 PM up to 10 mg CA4 / mL at 22.9 wt% and did not aggregate in PBS or 90% (v/v) human serum at 37°C for at least 24 h. In contrast, X-F127 PM decreased the unbound fraction of CA4 in whole blood (fu) and increased the mean plasma residence time and subsequent potency of CA4 against the vascular function and growth of primary murine 4T1 breast tumors over CA4 in F127 PM and water-soluble CA4P after IV administration.
  
  
  CONCLUSIONS
  Given that decreasing the fu is an indication of decreased drug release, peripherally cross-linking the shell of core-shell polymer micelles may be a simple approach to decrease premature release of physically loaded hydrophobic drug in the blood and increase subsequent potency in solid tumors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Wakaskar
authors.forename: Sai Praneeth R
authors.initials: SP
authors.lastname: Bathena
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Tallapaka
authors.forename: Vishakha V
authors.initials: VV
authors.lastname: Ambardekar
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.forename: Rhishikesh
authors.initials: R
authors.lastname: Thakare
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Simet
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Curran
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vetro
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005029:Ethylenediamines / Q000737:chemistry*; D005240:Feasibility Studies; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D020442:Poloxamer / Q000737:chemistry*; D012995:Solubility; D013267:Stilbenes / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D005029:Ethylenediamines; D008823:Micelles; D013267:Stilbenes; D020442:Poloxamer; C031234:ethylenediamine; C058728:fosbretabulin