Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric...

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Cancer Therapeutics

Background:

• Riboflavin transporters (RFTs) and riboflavin carrier protein (RCP) are upregulated in tumors, making them targets for nanomedicines.
• Effective nanomedicines require accumulation via EPR effect, extravasation, specific cell targeting, and internalization.
• Antibody-sized nanocarriers (10-15 nm) offer a balance between passive and active tumor targeting.

Purpose of the Study:

• To synthesize and evaluate riboflavin-targeted branched polyethylene glycol (PEG) polymers of different sizes for tumor targeting.
• To assess the biodistribution, accumulation, and cellular internalization of these nanocarriers in tumor models.
• To determine the influence of nanocarrier size and riboflavin targeting on cell- and compartment-specific uptake within tumors.

Main Methods:

• Synthesis of small (10 kDa, ~7 nm) and large (40 kDa, ~13 nm) riboflavin-targeted PEG polymers.
• Evaluation of nanocarrier biodistribution and tumor accumulation in mice bearing A431 and PC3 xenografts.
• Assessment of riboflavin (RF)-mediated targeting effects on accumulation and cellular internalization.
• Analysis of cell- and compartment-specific uptake based on nanocarrier size.

Main Results:

• The 40 kDa PEG showed higher tumor accumulation than the 10 kDa PEG, but active RF-targeting improved accumulation of the 10 kDa PEG.
• RF-targeting enhanced cellular internalization for both polymer sizes.
• Smaller 10 kDa RF-PEGs achieved higher intracellular amounts despite lower accumulation compared to larger PEG.
• Nanocarrier size dictated preferential uptake: 10 kDa targeted cancer cells, while 40 kDa targeted tumor-associated macrophages.

Conclusions:

• Nanocarriers sized like antibodies exhibit balanced passive accumulation, tissue penetration, and active targeting properties.
• Riboflavin-mediated targeting is a viable strategy for cancer cell targeting.
• High tumor accumulation does not guarantee high cellular uptake; nanocarrier size is critical for cell- and compartment-specific drug targeting.