Probing the fluorination effect on the self-assembly characteristics, in vivo fate and antitumor efficacy of paclitaxel prodrug nanoassemblies

Abstract

Rationale: Small-molecule prodrug nanoassembly is emerging as an efficient platform for chemotherapy. The self-assembly stability plays a vital role on the drug delivery efficiency of prodrug nanoassembly. It is reported that fluoroalkylation could improve the self-assembly stability of amphiphilic polymers by utilizing the unique fluorination effect. But the application of fluoroalkylation on small-molecule prodrug nanoassembly has never been reported. Methods: Here, fluoro-modified prodrug was developed by conjugating paclitaxel with perfluorooctanol (F8-SS-PTX), and the paclitaxel-octanol prodrug (C8-SS-PTX) was used as control. The fluoro-mediated self-assembly mechanisms were illustrated using molecular dynamics simulation. In addition, the impacts of fluoroalkylation on the pharmacy characters, in vivo fate and antitumor effect of small-molecule prodrug nanoassembly were investigated in details. Results: Fluoroalkylation significantly improved the self-assembly stability of F8-SS-PTX NPs both in vitro and in vivo, which could be attributed to the fluoro-mediated hydrophobic force and halogen bonds. The AUC0-24h and tumor accumulation of F8-SS-PTX NPs was 6-fold and 2-fold higher than that of C8-SS-PTX NPs, respectively. As a result, F8-SS-PTX NPs exhibited much better antitumor effect than C8-SS-PTX NPs and Abraxane. Conclusion: Fluoroalkylation could improve the self-assembly stability, in vivo fate, and antitumor efficacy of small-molecule prodrug nanoassemblies, which could be an effective strategy for the rational design of advanced nanomedicines.

Probing the Role of Connecting Bonds and Modifying Chains in the Rational Design of Prodrug Nanoassemblies

“…23 The disulfide bond showed better reduction sensitivity than thioether bond. 23,26,30 Therefore, the release rates of SA-SS-DTX NPs and HUA-SS-DTX NPs were faster than SA-S-DTX NPs. In addition, the structure of the modifying chain had little effect on the reduction sensitivity of prodrug nanoassemblies.…”

“…The H 2 O 2sensitive mechanism of the sulfide bonds has been demonstrably clarified in our previous work, since H 2 O 2 could oxidize the sulfur atoms to generate hydrophilic sulfoxide or sulphone, promote the rupture of the ester bond, and then facilitate the release of the free DTX (Figure 3C). 23,30,34 The essence of redox reactions is the gain and loss of electrons, that is, the rise and fall of the chemical valence of atoms. The chemical valence of sulfur in thioether bonds is −2, and the chemical valence of sulfur in disulfide bonds is −1.…”

“…Prodrugs usually consist of parent drugs, connecting bonds, and modifying chains . Both the connecting bonds and the modifying chains could affect the self-assembly ability, pharmacokinetics, and pharmacodynamics of the prodrugs. , Connecting bonds worked as linkages between parent drugs and modifying chains, which were crucial for the self-assembly ability and drug release of prodrugs . It has been reported that sulfide bonds, including thioether bonds and disulfide bonds, had a bond angle and dihedral angle closed to 90°, which could generate “structural defects” to enhance the self-assembly capacity of prodrugs. , In addition, it was found that the sulfide bonds could intelligently identify the tumor environment by responding to the elevated intracellular glutathione (GSH) and reactive oxygen species (ROS), thereby triggering the specific release of parent drugs. , Among them, the thioether bonds were more sensitive to oxidation, and the disulfide bonds were more sensitive to reduction .…”

“…Aliphatic chains are usually divided into straight chains and branched chains. At present, only straight aliphatic chains are commonly applied in the design of self-assembly prodrugs, while there are few reports about branched aliphatic chains. , We wondered whether the branched aliphatic chains with more steric hindrance could further promote the self-assembly of prodrugs. Systematic comparison of the influence of connecting bonds (thioether bond or disulfide bond) and modifying chains (branched chain or straight chain) on the self-assembly ability, pharmacokinetics properties, and antineoplastic activities of prodrug is of great significance for the rational design of prodrug nanoassemblies.…”

Sorafenib-Entrapped, Self-Assembled Pullulan–Stearic Acid Biopolymer-Derived Drug Delivery System to PLC/PRF/5 Hepatocellular Carcinoma Model

“…To visualise the ability of HCC cells to uptake Pull-SA nanoparticles, cells were seeded in an 8-well chamber at a density of 3×10 3 cells/well followed by incubation for 24 h for cells to attach. Then, coumarin-6-loaded Pull-SA nanoparticles formulated by the dialysis method, were added to cells (at a concentration of 250 ng/mL) 38 after sonication for 10 min and incubated for 4 h. After incubation, the cells were carefully rinsed twice with PBS to remove any unbound particles. The plasma membrane was stained red with Cell Mask TM (plasma membrane staining kit) for 10 min and the nucleus was counterstained blue with Hoechst for another 10 min.…”