Polysaccharide-Zein Composite Nanoparticles for Enhancing Cellular Uptake and Oral Bioavailability of Curcumin: Characterization, Anti-colorectal Cancer Effect, and Pharmacokinetics

Abstract

Curcumin (CUR) has demonstrated promising potential as a therapeutic agent against colorectal cancer (CRC). However, its intrinsic shortcomings, including oxidative instability, sensitivity to gastrointestinal (GI) hydrolytic/enzymatic action, and susceptibility to biotransformation and systemic elimination, have greatly undermined its value for application in clinical settings. The development of carriers, in particular oral formulations, for its efficient delivery has remained an important direction in nutraceutical research. In the present work, CUR-encapsulated nanoparticles were fabricated with zein alone (Zein-CUR) and with zein and a polysaccharide (PS) [gum Arabic (GA), hyaluronic acid (HA) and pectin (PC), respectively] (PS-Zein-CUR). Their physicochemical and biological properties were evaluated in a series of in vitro and in vivo assays. Dynamic light scattering analysis showed an increase in the particle size of the nanoparticles from 129.0 nm (Zein-CUR) to 188.8–346.4 nm (PS-Zein-CUR). The three PS-Zein-CUR formulations had significantly higher (17–22%) CUR encapsulation efficiency (EE) than Zein-CUR. Among them, HA-Zein-CUR exhibited the highest EE and loading capacity. Zeta potential and FTIR spectra indicated the involvement of electrostatic and hydrophobic interactions and hydrogen bonds in the formation of the PS-Zein-CUR. In human CRC cell lines (HCT8, HCT29, and HCT116), the three PS-Zein-CUR and CUR all effectively inhibited cell viability and colony formation (HA-Zein-CUR > PC-Zein-CUR > GA-Zein-CUR/CUR). HA-Zein-CUR and PC-Zein-CUR also resulted in significantly higher cellular uptake of CUR than GA-Zein-CUR and CUR. Simulated GI-digestion assay demonstrated significantly improved controlled-release properties of these two formulations. Further pharmacokinetics and tissue distribution assays in a CRC subcutaneous xenograft model in nude mice corroborated the enhanced pharmacokinetic properties of intragastric administration of HA-Zein-CUR compared with that of free CUR (3 times higher Cmax and 9.18 times higher plasma AUC). HA-Zein-CUR also led to enhanced delivery and accumulation of CUR in major organs/tissues, in particular CRC tumors and colon. These results together support that HA-Zein-CUR has promising potential as an oral agent for the control of CRC.

Hyaluronic Acid–Zein Core-Shell Nanoparticles Improve the Anticancer Effect of Curcumin Alone or in Combination with Oxaliplatin against Colorectal Cancer via CD44-Mediated Cellular Uptake

“…As shown in Figure 1 A, all the nanoparticles were evenly distributed in an aqueous solution. This was consistent with the field-emission scanning electron microscopy (FE-SEM) data in our recent study [ 26 ]. The encapsulation of zein visually improved the solubility of CUR, likely due to the high content of hydrophobic amino acid residues on zein molecules, which enable them to have high-affinity interaction with CUR [ 17 ].…”

“…The hydrogen bonding, electrostatic and hydrophobic interactions between the zein and polysaccharide (HA) molecules were likely responsible for the formation of the stable complexes in the nanoparticles [ 27 ]. These characteristic features were accompanied by a significant increase in the EE and LC of the nanoparticles (HZ-CUR) ( Table S1 ) and partly explained the favorable CUR release behavior during simulated gastrointestinal digestion in our previous study [ 26 ].…”

“…Unexpectedly, whether used alone or in combination with OXA, the anti-tumor effect of HZ-CUR was only moderately ( p < 0.28 vs. p < 0.21) but not significantly stronger than that of CUR. Although our preliminary pharmacokinetic study showed that HZ-CUR possessed better oral bioavailability than CUR [ 26 ], the data herein suggest that the low dosage of intragastric HZ-CUR probably did not lead to a sufficient level of CUR in the subcutaneous xenografts. Further studies are warranted to test whether higher oral dosages of the HZ-CUR would generate more significant therapeutic advantages over CUR.…”

“…Among the different routes of administration, oral delivery has been the most highly sought-after due to advantages such as convenience and good patient compliance. Our preliminary data showed that compared with free CUR, CUR-encapsulated HA–zein composite nanoparticles (HZ-CUR) exhibited significantly improved pharmacokinetics and tissue distribution behavior after oral administration in a subcutaneous CRC-xenograft model in mice [ 26 ]. These results suggest that HZ-CUR has promising potential as an efficient oral delivery system of CUR.…”

Complexation of curcumin with cyclodextrins adjusts its binding to plasma proteins

“…Curcumin is a natural phenolic compound that is claimed to possess various health benefits, including antioxidant, 1 antibacterial, 2 anticancer, 3 anti-inflammatory, 4 and anti-virus 5 activities. For this reason, it is widely used in the food, supplement, pharmaceutical, and cosmetic fields for its potential health benefits and as a natural pigment.…”