Optimizing Active Tumor Targeting Biocompatible Polymers for Efficient Systemic Delivery of Adenovirus

Area of Science:

• Biotechnology
• Nanomedicine
• Cancer Therapy

Background:

• Adenovirus (Ad) shows promise for cancer treatment but faces challenges in systemic delivery due to poor tumor tropism and liver accumulation.
• Targeted delivery of Ad is crucial for treating metastatic cancers effectively.

Purpose of the Study:

• To develop novel folic acid (FA)-conjugated polymers for enhanced systemic delivery of Ad.
• To investigate the impact of polymer charge and FA conjugation on Ad nanocomplexes' tumor tropism, cellular uptake, and biodistribution.

Main Methods:

• Synthesis of FA-conjugated methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-L-glutamate) (P5N2LG-FA and P5N5LG-FA) polymers with varying charge densities.
• Complexation of Ad with synthesized polymers to form nanocomplexes.
• Evaluation of cytotoxicity, transduction efficiency, cellular uptake mechanisms (folate receptor-dependent), blood circulation retention, and biodistribution in tumor-bearing models.

Main Results:

• FA-conjugated Ad nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) demonstrated superior transduction efficiency in folate receptor-overexpressing cancer cells compared to naked Ad.
• Systemic administration of Ad nanocomplexes resulted in increased blood circulation retention and significantly higher intratumoral accumulation.
• FA-functionalized nanocomplexes showed reduced accumulation in liver and normal organs compared to naked Ad, with optimized charge further minimizing off-target effects.

Conclusions:

• FA-conjugated polymers effectively enhance systemic Ad delivery, improving tumor targeting and reducing hepatotoxicity.
• Optimization of polyplex surface charge is critical for achieving efficient tumor-targeted systemic delivery of Ad nanocomplexes.
• These findings offer a promising strategy for developing effective Ad-based cancer nanomedicines.