Lipid grafts of egg-box complex: a new supramolecular biovector for 5-fluorouracil delivery.

ABSTRACT

An attempt was made to improve the pharmacokinetic behaviour of 5-fluorouracil (5-FU) by incorporating it into lipoprotein imitating synthetic carrier 'supramolecular biovector (SMBV)' which is an important prerequisite for achieving its better therapeutic performance against cancer. The polysaccharide core of SMBVs was prepared by ionotropic gelation technique by cross-linking polyguluronate units in the alginate molecules with calcium ions to form so called 'egg-box structure'. The formulation and process variables were optimized to obtain particles of nanometer size range. Hydrophobization was carried out by fatty-acylation on the surface followed by phospholipid coating. Palmitoyl polyethylene glycol (p-PEG) was anchored to impart stealth behaviour. The scanning electron microscopy showed discrete spheres of average diameter 748 nm. Polydispersity was estimated to be 0.37. Overall zeta potential was -21.3 mV. The drug loading capacity and encapsulation efficiency was found to be 10.0% and 97.9%, respectively. The release from drug solution (AP) followed zero-order kinetics. Higuchi release pattern was obtained for egg-box complex cores (AP1) while first-order pattern was followed for fatty acylated (AP2) and lipid coated cores before (AP3) and after p-PEG anchoring (AP4). The amount of drug liberated in 24 h was in the order AP > AP1 > AP2 > AP4 > AP3. The release pattern obtained was a combined effect of drug diffusion through egg-box matrix as well as partitioning in hydrophobic layer and p-PEG layer around the SMBV. The stability study showed negligible leakage and no appreciable change in particle size upon storage at different temperatures which is an indication of good stability of SMBV formulation. The plasma clearance data revealed increase in circulation half-life of drug and bioavailability. Tissue distribution data obtained was a result of competitive uptake of formulations from tissue macrophages and lymphatics depending upon its surface characteristics and residence period in vascular system. The enhanced delivery of drug to lymphatics and improvement in its half-life render SMBVs useful for control of metastasis and tumour growth.