title: Evaluation of triblock copolymeric micelles of δ- valerolactone and poly (ethylene glycol) as a competent vector for doxorubicin delivery against cancer.
abstract: BACKGROUND
  Specific properties of amphiphilic copolymeric micelles like small size, stability, biodegradability and prolonged biodistribution have projected them as promising vectors for drug delivery. To evaluate the potential of δ-valerolactone based micelles as carriers for drug delivery, a novel triblock amphiphilic copolymer poly(δ-valerolactone)/poly(ethylene glycol)/poly(δ-valerolactone) (VEV) was synthesized and characterized using IR, NMR, GPC, DTA and TGA. To evaluate VEV as a carrier for drug delivery, doxorubicin (DOX) entrapped VEV micelles (VEVDMs) were prepared and analyzed for in vitro antitumor activity.
  
  
  RESULTS
  VEV copolymer was successfully synthesized by ring opening polymerization and the stable core shell structure of VEV micelles with a low critical micelle concentration was confirmed by proton NMR and fluorescence based method. Doxorubicin entrapped micelles (VEVDMs) prepared using a modified single emulsion method were obtained with a mean diameter of 90 nm and high encapsulation efficiency showing a pH dependent sustained doxorubicin release. Biological evaluation in breast adenocarcinoma (MCF7) and glioblastoma (U87MG) cells by flow cytometry showed 2-3 folds increase in cellular uptake of VEVDMs than free DOX. Block copolymer micelles without DOX were non cytotoxic in both the cell lines. As evaluated by the IC50 values VEVDMs induced 77.8, 71.2, 81.2% more cytotoxicity in MCF7 cells and 40.8, 72.6, 76% more cytotoxicity in U87MG cells than pristine DOX after 24, 48, 72 h treatment, respectively. Moreover, VEVDMs induced enhanced apoptosis than free DOX as indicated by higher shift in Annexin V-FITC fluorescence and better intensity of cleaved PARP. Even though, further studies are required to prove the efficacy of this formulation in vivo the comparable G2/M phase arrest induced by VEVDMs at half the concentration of free DOX confirmed the better antitumor efficacy of VEVDMs in vitro.
  
  
  CONCLUSIONS
  Our studies clearly indicate that VEVDMs possess great therapeutic potential for long-term tumor suppression. Furthermore, our results launch VEV as a promising nanocarrier for an effective controlled drug delivery in cancer chemotherapy.
authors.affiliation: Chemical Biology, Molecular Medicine Division, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram-695 014, Kerala, India.
authors.forename: Lekha
authors.initials: L
authors.lastname: Nair K
authors.forename: Sankar
authors.initials: S
authors.lastname: Jagadeeshan
authors.forename: S Asha
authors.initials: SA
authors.lastname: Nair
authors.forename: G S Vinod
authors.initials: GS
authors.lastname: Kumar
mesh_terms: D017304:Annexin A5 / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry*
chemical_list: D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D011753:Pyrones; C052207:delta-valerolactone; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases