Targeted Albumin-Based Nanoparticles for Delivery of Amphipathic Drugs

Abstract

We report the preparation and physical and biological characterization of human serum albumin-based micelles of approximately 30 nanometers diameter for the delivery of amphipathic drugs, represented by doxorubicin. The micelles were surface conjugated with cyclic RGD peptides to guide selective delivery to cells expressing the alpha v/beta 3 integrin. Multiple poly(ethylene glycol)s (PEGs) with molecular weight of 3400 daltons were used to form a hydrophilic outer layer, with the inner core formed by albumin conjugated with doxorubicin via disulfide bonds. Additional doxorubicin was physically adsorbed into this core to attain a high drug loading capacity, where each albumin was associated with about 50 doxorubicin molecules. The formed micelles were stable in serum but continuously released doxorubicin when incubated with free thiols at concentrations mimicking the intracellular environment. When incubated with human melanoma cells (M21+) that express the alpha v/beta 3 integrin, higher uptake and longer retention of doxorubicin was observed with the RGD-targeted micelles, than in the case of untargeted control micelles, or free doxorubicin. Consequently the RGD-targeted micelles manifested cytotoxicity at lower doses of drug than control micelles or free drug.

Pharmacokinetic Characterization of Amrubicin Cardiac Safety in an Ex Vivo Human Myocardial Strip Model. II. Amrubicin Shows Metabolic Advantages over Doxorubicin and Epirubicin

“…Doxorubicin exhibited these characteristics (Xu et al, 2011;Salvatorelli et al, 2012). Amrubicin attained much lower levels in the membrane and was considerably less polar than doxorubicin ; therefore, amrubicin had more chances to produce H 2 O 2 through a canonical redox cycling mechanism.…”

Long-circulating self-assembled cholesteryl albumin nanoparticles enhance tumor accumulation of hydrophobic anticancer drug

“…Moreover, albumin accumulates in malignant and inflamed tissues through the EPR effect [14,15] transport of albumin-bound PTX is very likely mediated by the gp60 transcytosis pathway [15]. Several albumin nanoparticles have been reported for drug delivery, including octyl-albumin conjugation to improve albumin lipophilicity [11] and a doxorubicinalbumin conjugate with a cleavable bond [16].…”

Albumin pre-coating enhances intracellular siRNA delivery of multifunctional amphiphile/siRNA nanoparticles

“…Albumin is the most abundant and multifunctional protein in the human body, and it is widely used as a component in the development of drug delivery systems because of its dysopsonic activity, biodegradability, and biocompatibility. [15][16][17][18][19] Furthermore, albumin preferentially accumulates in tumor and inflamed tissues. 15 Thus, we have hypothesized and investigated that the incorporation of bovine serum albumin into targeted EHCO/siRNA nanoparticles enhances their cellular uptake in the presence of serum, and hence improves the gene-silencing efficiency of the siRNA/EHCO nanoparticles.…”

“…In addition to its nonimmunogenic and nontoxic properties, [15][16][17][18][19] albumin is inert to other serum molecules, and is used as a blocking agent in many in vitro molecularand cellular-based assays. Also, it has been incorporated into various drug delivery systems.…”

“…Also, it has been incorporated into various drug delivery systems. [15][16][17][18][19] Therefore, we used BSA to modify the targeted EHCO/siRNA nanoparticles, and determined the effect of serum albumin on the stability and intracellular uptake of the targeted nanoparticles. The size of the nanoparticles increased with BSA concentration, as shown in Figure 5A.…”