Intracarotid administration of short‐chain alkylglycerols for increased delivery of methotrexate to the rat brain

Abstract

1 The intracarotid administration of alkylglycerols has been reported previously by us to be a novel strategy for increased delivery of various chemotherapeutic drugs to the normal brain and brain tumors in rats. 2 Effectiveness and structure -activity relations of the most promising pentyl-and hexylglycerol derivatives have been elucidated in vivo by analyzing the transfer of methotrexate (MTX) across the blood -brain barrier (BBB) in normal rats. The effects were compared with BBB disruption using hypertonic mannitol or intracarotid infusion of bradykinin. Furthermore, toxicity of the alkylglycerols has been studied in long-term experiments. 3 Apart from 1-O-pentyldiglycerol, all alkylglycerols induced a concentration-dependent increase in MTX delivery to the brain varying from 1.1 to more than 300-fold compared to intra-arterial MTX alone. Enhanced barrier permeability rapidly approached baseline values within 5 and 120 min at the latest. Chemical structure, concentration, time schedule of injections and combination of different alkylglycerols were identified as instruments suited to regulate the MTX accumulation within a wide range. Mannitol 1.4 m resulted in very high MTX levels in the brain as observed using the highest concentrations of alkylglycerols. Intracarotid infusion of bradykinin had only a minor effect on the BBB. Using 1-O-pentylglycerol or 2-O-hexyldiglycerol, both cell culture experiments and long-term in vivo analyses including clinical, laboratory and histopathological evaluations revealed no signs of toxicity. 4 In summary, intracarotid short-chain alkylglycerols constitute a very effective and low toxic strategy for transient opening of the BBB to overcome the limited access of cytotoxic drugs to the brain.

Nanoparticles of alkylglyceryl-dextran-graft-poly(lactic acid) for drug delivery to the brain: Preparation and in vitro investigation

“…Considered non-toxic and non-immunogenic, dextran has been used historically as a safe plasma expander [18] and also to impart stabilisation in the blood-stream and ''stealth'' properties to injectable nanoparticles [19,20]. Among the materials investigated for enhancing drug penetration across the BBB, alkylglycerols have been shown to encourage a strong but transient increase in the transport of actives into the brain [21][22][23][24]. If co-administered into the right internal carotid artery, the same materials have been found to increase brain uptake of certain antineoplastic agents (such as cisplatin and methotrexate) or antibiotics (such as vancomycin and gentamycin) in C6 glioma bearing rats and animals with RG2 implanted tumours [25,26].…”

Encapsulation of fish oil with N-stearoyl O-butylglyceryl chitosan using membrane and ultrasonic emulsification processes

“…Stability of CS based carriers under gastrointestinal condition is very important for its oral administration (Mukhopadhyay, Mishra, Rana, & Kundu, 2012). The use of alkylglycerols has been shown to enhance the transport of active compounds into the brain because of their hydrophobic characteristics that facilitate entry though the lipid cell layer (Erdlenbruch, Jendrossek, Eibl, & Lakomek, 2000;Erdlenbruch et al, 2003). This property is further exploited by developing alkylglyceryl chitosans and alkylglyceryl N,N,N-trimethyl chitosans carriers for delivering drugs into the brain (Molnár, Barbu, Lien, Górecki, & Tsibouklis, 2010).…”

Increasing of Blood-tumor Barrier Permeability through Paracellular Pathway by Low-frequency Ultrasound Irradiation In Vitro

“…BTB is similar to BBB, which is located between tumor cells and microvessels formed by highly specialized endothelial cells. The permeability of BTB is higher than that of BBB (Yuan et al 1994), but it is still a significant barrier for therapeutic drugs to penetrate (Erdlenbruch et al 2003). …”