RESUMEN
The field of brain drug delivery faces many challenges that hinder development and testing of novel therapies for clinically important central nervous system disorders. Chief among them is how to deliver large biologics across the highly restrictive blood-brain barrier. Non-ionic surfactant vesicles (NISV) have long been used as a drug delivery platform for cutaneous applications and have benefits over comparable liposomes in terms of greater stability, lower cost and suitability for large scale production. Here we describe a glucosamine-coated NISV, for blood-brain barrier GLUT1 targeting, capable of traversing the barrier and delivering active antibody to cells within the brain. In vitro, we show glucosamine vesicle transcytosis across the blood-brain barrier with intact cargo, which is partially dynamin-dependent, but is clathrin-independent and does not associate with sorting endosome marker EEA1. Uptake of vesicles into astrocytes follows a more classical pathway involving dynamin, clathrin, sorting endosomes and Golgi trafficking where the cargo is released intracellularly. In vivo, glucosamine-coated vesicles are superior to uncoated or transferrin-coated vesicles for delivering cargo to the mouse brain. Finally, mice infected with Venezuelan equine encephalitis virus (VEEV) were successfully treated with anti-VEEV monoclonal antibody Hu1A3B-7 delivered in glucosamine-coated vesicles and had improved survival and reduced brain tissue virus levels. An additional benefit was that the treatment also reduced viral load in peripheral tissues. The data generated highlights the huge potential of glucosamine-decorated NISV as a drug delivery platform with wider potential applications.
Asunto(s)
Barrera Hematoencefálica , Virus de la Encefalitis Equina Venezolana , Animales , Glucosamina , Caballos , Ratones , Tensoactivos , TranscitosisRESUMEN
OBJECTIVE: The objective of the present study was to prepare cantharidin-entrapped non-ionic surfactant vesicles (CTD-NSVs) and evaluate their potential in enhancing the antitumor activities and reducing CTD's toxicity. METHODS AND RESULTS: CTD-NSVs were prepared by injection method. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry analysis showed that CTD-NSVs could significantly enhance in vitro toxicity against human breast cancer cell line MCF-7 and induce more significant cell-cycle arrest in G0/G1 phase. Moreover, Hoechst 33342 staining implicated that CTD-NSVs induced higher apoptotic rates in MCF-7 cells than free CTD solution. In vivo therapeutic efficacy was investigated in imprinting control region mice bearing mouse sarcoma S180. Mice treated with 1.0 mg/kg CTD-NSVs showed the most powerful antitumor activity, with an inhibition rate of 52.76%, which was significantly higher than that of cyclophosphamide (35 mg/kg, 40.23%) and the same concentration of free CTD (1.0 mg/kg, 31.05%). In addition, the acute toxicity and liver toxicity of CTD were also distinctly decreased via encapsulating into NSVs. CONCLUSION: Our results revealed that NSVs could be a promising delivery system for enhancing the antitumor activity and simultaneously reducing the toxicity of CTD.