Structural Modification of Nanomicelles through Phosphatidylcholine: The Enhanced Drug-Loading Capacity and Anticancer Activity of Celecoxib-Casein Nanoparticles for the Intravenous Delivery of Celecoxib.

Liuli Xv,Yan Wang,Chenghuan Yu,Peng Jin,Xinxin Qian,Yahui Zhang,Dingkui Qin,Qizhen Du

doi:10.3390/nano10030451

Abstract

This study aims to stabilize loaded celecoxib (CX) by modifying the structure of casein nanoparticles through phosphatidylcholine. The results show that Egg yolk phosphatidylcholine PC98T (PC) significantly increased the stability of CX-PC-casein nanoparticles (NPs) (192.6 nm) from 5 min (CX-β-casein-NPs) to 2.5 h at 37 °C. In addition, the resuspended freeze-dried NPs (202.4 nm) remained stable for 2.5 h. Scanning electron microscopy indicated that PC may block the micropore structures in nanoparticles by ultrasonic treatment and hence improve the physicochemical stability of CX-PC-casein-NPs. The stability of the NPs was positively correlated with their inhibiting ability for human malignant melanoma A375 cells. The structural modification of CX-PC-casein-NPs resulted in an increased intracellular uptake of CX by 2.4 times than that of the unmodified ones. The pharmacokinetic study showed that the Area Under Curve (AUC) of the CX-PC-casein-NPs was 2.9-fold higher in rats than that of the original casein nanoparticles. When CX-PC-casein-NPs were intravenously administrated to mice implanted with A375 tumors (CX dose = 16 mg/kg bodyweight), the tumor inhibition rate reached 56.2%, which was comparable to that of paclitaxel (57.3%) at a dose of 4 mg/kg bodyweight. Our results confirm that the structural modification of CX-PC-casein-NPs can effectively prolong the remaining time of specific drugs, and may provide a potential strategy for cancer treatment.

Highlights

Caseins have been widely studied and used due to their biocompatibility, biodegradability, bioresorbability, and low price, allowing for simple production
SEM shows that phosphatidylcholine (PC) blocks gaps in the nanoparticles to improve nanoparticle stability
The stability of CX-casein nanoparticles was found to be positively correlated with their inhibition activity against human malignant melanoma A375 cells and to eliminate the local high CX concentration at the injection site

Summary

Introduction

Caseins have been widely studied and used due to their biocompatibility, biodegradability, bioresorbability, and low price, allowing for simple production. Casein micelles show a porous inner structure [3,4] with irregular channels (d > 5 nm) and inner cavities (d = 20–30 nm) [3] These features make caseins a promising matrix candidate for drug encapsulation [5,6]. Casein nanoparticles loaded with hydrophobic drugs usually show low structural stability. When the drug-loaded casein nanoparticles were placed in the medium at 37 ◦C, most of the drugs, such as paclitaxel [10], celecoxib, and vitamin D (unpublished data), were quickly released within 5 min. This may result in unfavorable release profiles for specific drugs, as the bioavailability, targeting ability, and local toxicity should be considered. It is critical to enhance the physicochemical stability of drug-loaded casein nanoparticles for drug delivery in vivo via the structural modification of casein nanoparticles

Objectives

Methods

Results

Conclusion