A Biomimetic Micro-Nano System Maximizing 'Active Transport and Retention' Effect in Solid Tumors.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Drug Delivery

Background:

• The Active Transport and Retention (ATR) principle aims to improve nanodrug tumor penetration via transcytosis.
• Current ATR applications face challenges including poor tumor homing, endothelial efflux, and uncontrolled transcytosis.
• Tumor heterogeneity complicates effective nanodrug delivery and therapeutic outcomes.

Purpose of the Study:

• To develop a bio-mimetic micro-nano system (PG@BAM-L_RC) that overcomes ATR limitations for enhanced nanodrug tumor delivery.
• To leverage platelet-derived microcarriers (PG) for tumor homing and MMP-9 responsive release.
• To engineer nanoliposomes (L_RC) for targeted transendothelial transport and superior intracellular retention.

Main Methods:

• Constructed a micro-nano system (PG@BAM-L_RC) using nanoliposomes (L_RC) and berbamine (BAM) within platelet-derived microcarriers (PG).
• Utilized BAM to modulate apical recycling endosomes for basal transendothelial transport and an arginine-lysine-lysine-arginine-cysteine (Cys) ligand for Golgi-targeted transport.
• Incorporated furin-mediated cleavage of the Cys ligand to halt transcytosis and enhance intracellular drug retention within tumor cells.
• Evaluated the system in four heterogeneous murine tumor models, focusing on an orthotopic pancreatic tumor with minimal EPR effect.

Main Results:

• PG@BAM-L_RC demonstrated enhanced tumor accumulation and therapeutic efficacy compared to control groups (L_RC, PG@L_RC, PG@BAM-L_RC without cleavage).
• The system effectively utilized the ATR principle, showing significant tumor targeting even in tumors with minimal enhanced permeability and retention (EPR) effect.
• Furin-mediated Cys-cleavage significantly improved intracellular drug retention within tumor cells.

Conclusions:

• The developed PG@BAM-L_RC system represents a robust strategy for tumor-targeted nanodrug delivery by optimizing the ATR mechanism.
• This approach effectively addresses tumor heterogeneity and overcomes limitations associated with nanodrug transcytosis and retention.
• The study highlights the potential of bio-mimetic micro-nano systems for improving cancer nanotherapeutics.