Engineering stable prodrug self-assemblies by introducing the bromination effect.

Area of Science:

• Nanomedicine
• Drug Delivery
• Cancer Therapy

Background:

• Prodrug nano-self-assemblies offer promise for cancer treatment but face challenges in stability, prolonged circulation, and tumor accumulation.
• Rational design of assembly modules is crucial for balancing forces during self-assembly.

Purpose of the Study:

• To design and synthesize novel paclitaxel prodrugs with enhanced self-assembly properties for improved cancer therapy.
• To investigate the role of bromination in the assembly module on nanoparticle stability and anti-cancer efficacy.

Main Methods:

• Synthesis of two paclitaxel prodrugs utilizing a disulfide bond for activation and palmitic acid or 2-bromopalmitic acid as assembly modules.
• Characterization of nano-assemblies for stability, blood circulation, and tumor accumulation.
• Evaluation of anti-cancer efficacy in vitro and in vivo.

Main Results:

• Incorporation of a bromine atom in the assembly module significantly increased hydrophobicity and induced steric hindrance.
• These modifications enhanced both driving and repulsive forces, leading to highly stable prodrug nano-assemblies (PA(Br)-SS-PTX NPs).
• Optimized nano-assemblies demonstrated superior blood circulation and tumor accumulation, resulting in potent anti-cancer efficacy.

Conclusions:

• Bromination of assembly modules is a promising strategy to enhance the stability and performance of prodrug nano-self-assemblies.
• This approach leads to effective nanomedicines with improved pharmacokinetic profiles and anti-cancer activity.
• The findings highlight the importance of chemical structure optimization for developing advanced cancer therapeutics.