Are similar nanoforms comparable in biodistribution? Data-driven approaches for optimizing nanomedicine design

Area of Science:

• Nanomedicine
• Drug Delivery
• Biomedical Engineering

Background:

• Rational design of tumor-targeted nanomedicines is crucial for effective cancer therapy.
• Quantitative frameworks linking nanoform properties to biodistribution are needed.
• Current understanding of biodistribution determinants is limited.

Purpose of the Study:

• To identify physicochemical and study design factors governing nanomedicine biodistribution across multiple tissues.
• To dissect the determinants of tissue-level distribution patterns for 200 diverse nanoforms in tumor-bearing mice.
• To establish quantitative relationships between nanoform properties and delivery efficiency to tumors and off-target organs.

Main Methods:

• Integrated univariate screening, multivariate permutational analysis, and unsupervised multivariate statistical analysis.
• Analyzed biodistribution data (% injected dose) in tumor, liver, spleen, lung, kidney, and heart.
• Utilized a curated dataset of 200 organic, inorganic, and hybrid nanoforms tested in mice.

Main Results:

• Cancer type, core material, hydrodynamic diameter, zeta potential, and dose significantly impact biodistribution.
• Liver and spleen uptake showed strong correlation (ρ = 0.76), while tumor uptake had minimal correlation with off-target organs (ρ < 0.40).
• Optimal tumor-efficient nanoforms exhibited intermediate size (100-440 nm), moderate dose (1-50 mg/kg), and near-neutral surface charge (-15 to +10 mV), achieving up to 9% tumor uptake with lower liver/spleen accumulation.

Conclusions:

• Tumor delivery mechanisms are partially distinct from systemic clearance pathways.
• A specific design region (intermediate size, moderate dose, near-neutral charge) shows promise for enhanced tumor targeting.
• Findings provide a quantitative landscape for hypothesis-driven nanoform development and clinical translation, requiring prospective validation.