Structural Characterization of 5-fluorouracil in the Self-Assembly of the Pluronic Biomedical Hydrogels for Prolonged Drug Release

Chemotherapy is the medical treatment for human cancer through intravenous injection or oral administration. However, high dosage of chemotherapeutic drugs was required to de delivered to the malignant tumor. In recent years, the use of polymer composites for local and sustained drug release has become leading research to carry chemotherapeutic drugs without concentrated dosage. Pluronic biomedical hydrogels (PBHs) was proposed to be deployed on the tumor site for precision medicine as a targeted delivery for clinical and practical applications. PBHs also served as a microenvironment and a drug delivery system offering many attractive benefits such as intrinsic biocompatibility, ease of preparation, scalable production. Binary blending of biocompatible Pluronic® F127 and Pluronic® L121 is the main ingredient in the PBHs. Based on the same formulation, the addition sequence of fluorouracil (5-FU) was deployed in three ways when it was individually incorporated with F127-(5-FU), L121-(5-FU), as well as the binary mixing F127-L121-(5-FU).<br/>Small angle X-ray scattering (SAXS) and 19F-{1H} heteronuclear Overhauser enhancement spectroscopy (HOESY) was used to discover the self-assembled structures of the PBHs. According to the SAXS results, structural changes of the micelle and the lamellar affected the distribution of 5-FU. F127-L121-(5-FU) has the fastest drug release rate owing to the undulated amphiphilic boundary. In contrast, L121-(5-FU) has a prolonged drug release rate at 67% for one month of the continuous drug release experiment because the flat lamellar amphiphilic boundary which slows the migration of 5-FU from the hydrophobic core.<br/>Further, HOESY was used to study the micellular environment of the F-containing chemotherapeutic drug 5-FU in PBHs. Results show that the diffusion of the 5-FU medicine in the Pluronic micelles will move across the interface between the hydrophilic corona and the hydrophobic core with respect to elevated temperatures. At 25 °C, the drug loading location of the 5-FU medicine is dominated by PEO segments. As the temperature increases from 25 to 45 °C, the 5-FU medicine migrates aggressively to the hydrophobic core inside the micelles. The 5-FU medicine was embedded into the PPO segment of Pluronic® polymers above 37 °C as a stable micellization. The precise 5-FU loading in the hydrophobic area gives rise to prolonged and sustained drug release in rountine clinical practice. Thus, the drug loading location and drug–carrier interactions can be designed to deliver drugs at predetermined release rates. The chemotherapeutic drugs of 5-fluorouracil (5-FU) were released from PBHs nearly one month without continuous supplementary.<br/>Also, the inhibition of multidrug resistance was developed in this study. The effective ingredient of L121 inhibited multidrug resistance in human pancreatic cancer and caused the malfunction of the ATP binding cassette subfamily C (ABCC) transporter as evidenced by the flow cytometer studies. PBHs effectively suppresses the function of ABCC transporter up to 25 days. 5-FU can accumulate in the cancer cells of AsPC-1 and PANC-1 at a designated effective concentration. This synergy effect of the continuous drug release of 5-FU and intrinsic cytotoxic effects of L121 could inhibited the function of a multi-drug resistance regarding ABCC transporter. Then, a surgical dressing was prepared by 3D bio-printing technology with PBHs cross-linked by sodium alginate. Results show that the surgical dressing of 24 layers with 10 mm x 10 mm would continuously release 5-FU in effective anticancer concentration for six days. The flexibility of the PBHs makes tailored drug delivery system possible and improve the life quality of patients. Sustained and prolonged drug release and 3D printable surgical dressing was completed.