High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Solid tumors present significant challenges for therapeutic biomacromolecule delivery due to complex microenvironments.
• Efficient penetration of drugs into tumors is crucial for effective treatment.
• Nanoparticles offer a potential solution for targeted drug delivery and enhanced tumor penetration.

Purpose of the Study:

• To develop active-transporting nanoparticles for efficient delivery of biomacromolecular drugs into solid tumors via cell transcytosis.
• To create and evaluate cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with varying peripheral amino acids.
• To demonstrate nanoparticle-mediated tumor active transport using an antibody targeting programmed-death ligand 1 (αPD-L1).

Main Methods:

• Preparation of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids.
• High-throughput screening to evaluate nanodot-induced cell endocytosis, exocytosis, and transcytosis.
• Conjugation of optimized nanodots (G5-R) with αPD-L1 to create αPD-L1-G5-R for assessing nanoparticle-mediated tumor transport.

Main Results:

• Optimized nanodots (G5-R) demonstrated efficient induction of cell transcytosis.
• αPD-L1-G5-R significantly enhanced tumor penetration through adsorption-mediated transcytosis (AMT).
• In mice with CT26 tumors, αPD-L1-G5-R improved immune checkpoint blockade, reduced recurrence, and prolonged survival.

Conclusions:

• Active-transporting nanodots are effective platforms for delivering therapeutic biomacromolecules into solid tumors.
• Nanoparticle-mediated transcytosis enhances drug distribution within the tumor microenvironment.
• This approach shows promise for local immunotherapy of residual tumors post-surgery, improving treatment outcomes.