Tumor micro-environment targeted collagenase-modified albumin nanoparticles for improved drug delivery

Abstract

Gemcitabine is a deoxycytidine analogue used as an adjunct therapy in the treatment of various solid tumors. The therapeutic efficacy of this drug is compromised because of its short circulation half-life (∼17 min), fast metabolic degradation and dose dependent adverse effects. Also, there are various barriers in the tumor microenvironment which limit the drug delivery to the solid tumor. Keeping these aspects into consideration, in the present investigation, protease (collagenase) coated gemcitabine-loaded human serum albumin (HSA) nanoparticles (CG-HSANPs) were prepared to improve the drug delivery to the solid tumor compared with uncoated gemcitabine-loaded HSA nanoparticles (G-HSANPs). The desolvation technique was used to develop nanocarriers, which were evaluated for physicochemical properties such as average particle diameter, surface charge, morphology, drug loading and in vitro drug release. The average particle diameter of G-HSANPs and CG-HSANPs was found to be 160.5 ± 4.1 and 181.7 ± 2.54 nm, respectively. The morphology of nanocarrier was investigated by transmission electron microscopy (TEM) and the nanoparticles were also evaluated using differential scanning calorimetry (DSC). The in vitro antiproliferative activity showed comparable cytotoxicity of CG-HSANPs, G-HSANPs and native drug. The fluorescence microscopy showed uptake of collagenase coated HSA nanoparticles (C-HSANPs) and uncoated HSA nanoparticles (HSANPs) in MiaPaCa-2 cells and there was higher nuclear fragmentation, generation of reactive oxygen species and perturbation in mitochondrial membrane potential of CG-HSANPs compared to the native drug. Further, C-HSANPs exhibited improved tumor spheroid penetration as compare to HSANPs. The present study demonstrated the potential of CG-HSANPs as a carrier for improved drug delivery.