Design of pH-sensitive biomimetic platelet membrane liposome encapsulating curcumin for targeted liver cancer treatment

Abstract

Cancer is a cause of death as well as a major obstacle to increase the life expectancy in countries around the world. In this study, liver cancer was focused on because it is one of the most fatal cancers, for which chemotherapy is usually the best choice. However, severe side effects are usually observed in cancer patients undergoing chemotherapy. Natural products and traditional herbal medicines can offer novel possibilities for cancer treatments to overcome the drawbacks of conventional chemotherapies. Curcumin, extracted from the roots of Curcuma longa Linn, has been known to have antitumor activity and good safety. Nevertheless, the quick clearance, low bioavailability, as well as poor tumor accumulation hindered clinical application of curcumin. Evidence has shown that platelet membrane camouflaged nanoparticle possesses improved pharmacokinetic behavior and favorable tumor targeting. In this study, novel platelet membrane bioinspired liposomes were fabricated to ameliorate the precise delivery of curcumin to tumors and enable a more effective cancer treatment. Therefore, in order to enhance the pharmacokinetics, tumor targeting, as well as anticancer cytotoxicity of curcumin, curcumin-encapsulated platelet membrane biomimetic lipid vesicle was firstly developed. The results showed the nanoparticle exhibited a size of 163.2 nm and zeta potential of -31.8 mV. Western blotting result suggested that platelet membrane proteins had been successfully transferred to the resultant nanoparticle. The drug release of curcumin-encapsulated platelet membrane biomimetic lipid vesicle in vitro showed about 50% of the loaded curcumin was reserved over the course of 4 days. This nanoparticle could improve the bioavailability and extend the circulation time of curcumin. The values of area under the concentration-time curve (AUC), mean residence time (MRT), and clearance rate (Cl) of this bioinspired formulation were markedly ameliorated compared with free curcumin. Biodistribution results further demonstrated the in vivo long retention of this nanocarrier. In addition, the uptake of curcumin-encapsulated platelet membrane biomimetic lipid vesicle by hepatocellular carcinoma Huh-7 cells was enhanced compared with traditional curcumin-encapsulated liposome. The mechanism may be related to interaction between cancerous CD44 receptor and platelet P-selectin. And based on higher cellular uptake, the cytotoxicity of the developed formulation against Huh-7 cells was also enhanced. Likewise, the developed nanoparticle also exhibited enhanced cytotoxicity in human ovarian SK-OV-3 cancer cells as well as human breast MDA-MB-231 cancer cells. However, the drug release behaviors of curcumin-encapsulated platelet membrane biomimetic lipid vesicle were limited, and the anticancer effects of this formulation remain need to be further studied. Thus, curcumin-loaded platelet membrane bioinspired chitosan-modified liposome was constructed. The hydrodynamic size and zeta potential of this nanoparticle were 162.8 nm and 22.2 mV, respectively. Confocal microscopy analysis and Western blot analysis demonstrated the successful preparation of this nanoparticle. Moreover, Western blotting results revealed that bioinspired liposomes had reserved the characteristic proteins in the platelet membrane, including platelet-specific CD41, immunomodulatory CD47, as well as cancer-targeted P-selectin. The incorporation of chitosan enabled this bioinspired liposome to release cargo rapidly under mild acidic tumor conditions, that indicated the pH-responsive drug release capacity of curcumin-loaded platelet membrane bioinspired chitosan-modified liposome. Confocal laser scanning microscope images showed the fabricated bioinspired liposome could escape the uptake of RAW264.7 macrophages and drive cargoes into hepatocellular carcinoma HepG2 cells efficiently. Similar to curcumin-encapsulated platelet membrane biomimetic lipid vesicle, the developed nanoparticle could improve the pharmacokinetics of curcumin. In vivo images, ex vivo images, and immunofluorescence assay suggested that the developed bioinspired liposome exhibited a superior targeting ability. Both in vitro and in vivo investigations revealed that curcumin-loaded platelet membrane bioinspired chitosan-modified liposome could obviously enhance the anti-liver cancer effect of curcumin, which might ascribe to the platelet membrane camouflage as well as chitosan modification. In addition, both in vitro and in vivo assays certified the developed nanoparticle showed good safety. In summary, curcumin-loaded platelet membrane bioinspired chitosan-modified liposome exhibited favorable tumor affinity, prolonged circulation time, improved bioavailability, and high biocompatibility resulting from its platelet membrane cloaking. Moreover, the additional pH-responsive function was effectually translocated into this nanosystem, leading to quicker and completer release of cargoes. This developed delivery system showed enhanced antitumor efficacy compared to synthetic liposomes and traditional biomimetic liposome, which could provide a good option for effective cancer treatment and natural compound curcumin delivery.