(584w) Human Serum Albumin (HSA) Nanoparticles Stabilized With Intermolecular Disulfide Bonds

Proteins as matrices for drug delivery have many advantages including biodegradability, biocompatibility, non-toxic and amenability to surface modification. Albumin nanoparticles have been regarded as an ideal drug carrier material: 1) HSA is an endogenous protein, non-toxic and non-antigenic. 2) many metabolic compounds and therapeutic drugs, such as bilirubin, penicillins, sulphonamides and benzodiazepines, are extensively bound to and transported by this protein in blood circulation, which makes HSA a natural drug carrier. 3) HSA has active targeting ability via gp60 receptor-mediated transcytosis, which may enable tumor targeting.

The intermolecular disulfide bonds formed between the albumin sulfhydryl groups are the ideal stabilization strategy since it can not only stabilize the particles against dilution in vivo and the possible organic solvent used in drug loading, but also make the particles have the redox responsiveness in the reducing environment. However, so far there is no satisfying chemistry to crosslink albumin in order to stabilize the nanoparticles against dilution in circulation. Even the one used in clinic, Abraxane, has been shown to dissociate completely after dilution and hence lost its potential advantage in tumor targeting via the enhanced permeation and retention (EPR) effect. 

In this work, we proposed and demonstrated the feasibility to use albumin’s own thiol groups to form inter-protein disulfide crosslinks and stabilize the albumin nanoparticles against dilution and organic solvents. The formed nanoparticle would dissolve in the physiologically-relevant reducing environment and release albumin monomers. Throughout the fabrication process, only glutathione and ethanol/tertiary butanol were used, and no toxic chemical was involved, making it especially suitable for in vivo applications.

In addition, we used our technique to load curcumin and paclitaxel, forming the CCM-HSA-NPs PTX-HSA-NPs to demonstrate the applications of our HSA-NPs. The stability of the drug-HSA-NPs in different solvents and the drug loading efficiency were evaluated.     

We believe that our method represents a very valuable progress in nanomedicine materials chemistry and should be interesting to the fields of nanomedicine, drug delivery and biomaterials.