Carboxymethyl Dextran-modified Doxorubicin Liposomes And Its Properties

Liposomes have been widely used for drug delivery due to their unique properties, such as high biocompatibility, high entrapment efficiency of hydrophilic therapeutic agents, favorable pharmacokinetic profile, protecting encapsulated drugs from external conditions, and controlled release at specific disease sites in the body. However, un-coated liposomes (UC-LIPs) are unstable in the presence of plasma serum, which hampers their use for controlled release of active drugs. Therefore, surface modification is very important for liposomal carriers to enhance the stability and achieve superior efficiency in tumor therapy. Dextran is a linear polysaccharide with non-toxicity, non-immunogenicity, biocompatibility and biodegradability, which is extensively used in pharmaceutics fields. The aim of this work is to prepare carboxymethyl dextran (CMD)-coated liposomes (CMD-LIPs) to improve the stability and controlled release of the liposomes.Firstly, dextran was carboxymethylated and then provided with hydrophobic moieties by reacting with oleylamine to produce amphiphilic CMD. The structure of the synthetic products was characterized by IR and XH NMR spectrum. At the same time, we measured the degree of substitution (DS) of carboxymethyl and the hydrophobic oleyl group. The result showed that the DS of carboxymethylation was 0.30, while the DS of amidation was 0.10.Secondly, phosphatidylcholine, amphiphilic CMD and cholesterol were used to prepare CMD-LIPs via the thin-lipid film hydration method. The properities of liposomes were measured by AFM and Malvern Nano ZS Zetasizer. The results indicated that CMD-LIPs had a narrow distribution with approximately 100 run. CMD-LIPs are very stable against long-term storage at 4℃and can be re-dispersibility after lyophilization. Besides, SPR was employed to study the BSA adsorption on UC-LIPs, CMD-LIPs and anti-BSA attached CMD-LIPs. Compared with UC-LIPs, CMD-LIPs show negligible BSA adsorption, which indicated CMD-LIPs exhibit long circulation time in the blood. Moreover, the result revealed the surface of CMD-LIPs can be easily further modified with active ligands for drug targeting.Lastly, we prepared DOX-loaded CMD-LIPs by remote loading method with an ammonium sulfate gradient. The DOX-loaded CMD-LIPs exhibited excellent stability against storage and re-dispersibility after lyophilization. Compared with DOX-loaded UC-LIPs, CMD-LIPs showed a sustained and pH-responsive drug release profile. At physiological pH, DOX release rate of CMD-LIPs was much slower than that of at acidic pH, which would lead to selectively release in tumor cells. MTT revealed that the cytotoxicity of DOX-loaded CMD-LIPs on Hela cells was time-and concentration-dependent. In addition, CMD-LIPs can be used as carriers for other drugs, nutrients and dyes.