Hydrophobically Modified Paclitaxel Prodrug Enables Ultrahigh Drug Loading Driven by Polarity Redistribution

Area of Science:

• Nanomedicine
• Drug Delivery
• Materials Science

Background:

• Controllable drug loading and self-assembly are crucial for nanomedicine efficacy.
• Hydrophobic drugs like paclitaxel (PTX) present challenges in achieving high drug loading capacity (DLC) and stable self-assembly.
• Existing methods struggle with uniform nanoparticle formation and high DLC for hydrophobic chemotherapeutics.

Purpose of the Study:

• To develop a prodrug design strategy to enhance drug loading efficiency and self-assembly for hydrophobic drugs.
• To create uniform nanoparticles with high DLC exceeding 78 wt % for paclitaxel (PTX).
• To investigate the self-assembly mechanism using molecular dynamics simulations and validate the strategy through in vitro and in vivo studies.

Main Methods:

• Prodrug design strategy for hydrophobic chemotherapeutics.
• Spontaneous self-assembly into uniform nanoparticles (100-200 nm).
• Molecular dynamics simulations to understand self-assembly.
• In vitro and in vivo antitumor evaluations.

Main Results:

• Designed prodrugs self-assemble into uniform nanoparticles with ultrahigh DLC (>78 wt %).
• Molecular dynamics simulations revealed hydrophobic modifications stabilize assembled structures by orienting polar moieties outward.
• The strategy demonstrated significant potential in comprehensive in vitro and in vivo antitumor evaluations.

Conclusions:

• The prodrug design strategy offers a simple and versatile platform for optimizing nanomedicine formulations.
• This approach advances the clinical translation of high-DLC paclitaxel (PTX) prodrug nanomedicines.
• The established design principles are applicable to a broader range of hydrophobic drugs for nanomedicine development.