Evaluation of interstitial protein delivery in multicellular layers model

Area of Science:

• Biomedical Engineering
• Drug Delivery
• Oncology

Background:

• Limited efficacy of protein anticancer drugs is due to poor tumor tissue distribution.
• Effective delivery of protein therapeutics to tumor interstitium remains a challenge.

Purpose of the Study:

• To evaluate interstitial delivery of model proteins with varying molecular size and bioaffinity in human cancer multicellular layers (MCLs).
• To explore strategies for enhancing protein drug penetration in tumor tissues.

Main Methods:

• Cultured human cancer MCLs in Transwell inserts and exposed to four model proteins: TRAIL, cetuximab, RNase A, and IgG.
• Utilized fluorescence microscopy and immunohistochemistry to assess protein penetration.
• Investigated effects of increased dosage, PEGylation, nanogel formulation, and penetration enhancers.

Main Results:

• TRAIL and cetuximab showed partial MCL penetration; RNase A and IgG showed insignificant penetration.
• PEGylated proteins and nanogel formulations significantly improved penetration.
• Paclitaxel pretreatment enhanced IgG penetration, while high bioaffinity led to front-layer sequestration.

Conclusions:

• MCL culture is a viable model for evaluating protein drug delivery in the tumor interstitium.
• Bioaffinity, rather than size, influences penetration, but high affinity can cause drug sequestration.
• Strategies like polymer conjugation, nanoformulation, and penetration enhancers are crucial for improving anticancer protein drug delivery.