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Disposition characteristics of macromolecules in tumor-bearing mice
Y Takakura1, T Fujita, M Hashida
1Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Abstract:
As part of the strategy for the design of macromolecular carriers for drug targeting, the disposition characteristics of macromolecules were studied in mice bearing tumors that served as target tissues. Eight kinds of macromolecules including four polysaccharides and four proteins with different molecular weights and electric charges were used; tissue distribution and tumor localization after intravenous injection were studied. Pharmacokinetic analysis revealed that the tissue radioactivity uptake rate index calculated in terms of clearance was different among the tested compounds; especially, the urinary radioactivity excretion clearances and the total hepatic radioactivity uptake clearances varied widely. Compounds with low molecular weights (approximately 10 kD) or positive charges showed lower tumor radioactivity accumulation; radioactivity was rapidly eliminated from the plasma via rapid urinary excretion or extensive hepatic uptake, respectively. On the other hand, large and negatively charged compounds, carboxymethyl dextran, bovine serum albumin, and mouse immunoglobulin G, showed higher radioactivity accumulation in the tumor (calculated total amounts were 15.6, 10.8, and 20.8% of the dose, respectively) and prolonged retention in the circulation. These results demonstrated that the total systemic exposure rather than the uptake rate index was correlated with total tumor uptake. Molecular weight and electric charge of the macromolecules significantly affected their disposition characteristics and, consequently, determined radioactivity accumulation in the tumor. It was concluded that a drug-carrier complex designed for systemic tumor targeting should be polyanionic in nature and larger than 70,000 in molecular weight.
Insights
Macromolecule properties like size and charge influence drug delivery. Large, negatively charged molecules accumulate more in tumors, suggesting optimal drug carriers should be polyanionic and over 70,000 molecular weight.
Area of Science:
- Pharmacology
- Biomedical Engineering
- Drug Delivery Systems
Background:
- Designing effective macromolecular carriers for targeted drug delivery is crucial.
- Understanding the disposition characteristics of macromolecules is essential for optimizing tumor targeting strategies.
Purpose of the Study:
- To investigate how molecular weight and electric charge of macromolecules affect their distribution and tumor localization in mice.
- To identify optimal characteristics for macromolecular drug carriers for systemic tumor targeting.
Main Methods:
- Studied tissue distribution and tumor localization of eight different macromolecules (polysaccharides and proteins) in tumor-bearing mice after intravenous injection.
- Performed pharmacokinetic analysis, including clearance rates and radioactivity uptake in various tissues.
- Correlated macromolecule properties (molecular weight, charge) with tumor accumulation and plasma retention.
Main Results:
- Macromolecules with low molecular weight (approx. 10 kD) or positive charges showed reduced tumor accumulation and rapid elimination.
- Large, negatively charged macromolecules (carboxymethyl dextran, bovine serum albumin, mouse immunoglobulin G) exhibited higher tumor accumulation (10.8–20.8% of dose) and prolonged circulation.
- Total systemic exposure, not just uptake rate, correlated with tumor uptake.
Conclusions:
- Macromolecular properties, specifically molecular weight and electric charge, significantly influence disposition and tumor accumulation.
- Optimal drug carriers for systemic tumor targeting should be polyanionic and have a molecular weight exceeding 70,000.
- These findings provide critical insights for designing advanced drug delivery systems for cancer therapy.