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Impact of Tumor-specific Targeting on the Biodistribution And Efficacy of siRNA Nanoparticles Measured by Multimodality In Vivo Imaging


With the rapid development of technologies, the targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. This article is written by a research team from the California Institute of Technology, the University of California, and the University of Freiburg, who uses positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA.

Targeted drug delivery is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. There are different types of delivery vehicles, such as polymeric micelles, liposomes, lipoprotein-based drug carriers, dendrimers, etc.

Targeted nanoparticles are a promising class of new experimental medicines that have the potential to provide increased efficacy and lower toxicity relative to conventional therapeutics. Through the enhanced permeability and retention (EPR) effect, macromolecular therapeutics tend to accumulate within tumors after systemic delivery. As such, nanoparticles represent an approach for the delivery of large drug payloads to tumors.

This research designed a mathematical model of targeted nanoparticle behavior, which can describe some results and illustrate concepts that can be applied generally to the design of targeted therapeutics for oncology applications.

1. Formation of 64Cu-Labeled Nanoparticles Using 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid (DOTA)-siRNA

DOTA was conjugated to the 5 end of an siRNA sequence targeting luciferase mRNA, and nanoparticles were successfully formed with DOTA-siRNA.

2. Biodistribution of Naked siRNA and siRNA Nanoparticles After i.v. Administration

Micro-PET (positron emission tomography)/CT (computer tomography) was used to examine the kinetics of the biodistribution and tumor localization of 64Cu-labeled molecules after i.v. injection in mice. The total dose of siRNA within the nanoparticles was the same as that used for naked siRNA, and 50% of the total siRNA was DOTA-siRNA. The biodistribution of the 64Cu-DOTA-siRNA packaged into Tf (transferrin)-targeted nanoparticles appeared similar to that observed for naked 64CuDOTA-siRNA, except that there was slightly higher liver accumulation and a delayed peak in kidney accumulation.

3. Tumor Localization and Function of Targeted Versus Nontargeted siRNA Nanoparticles

A multimodality imaging approach was used to investigate the biodistribution and functional activity of siRNA delivered by Tf-targeted or nontargeted nanoparticles, including microPET/CT and BLI (bioluminescent imaging). The observed data provide strong evidence suggesting that Tf-targeted nanoparticles were able to deliver more functional siRNA into the tumor cells than nontargeted nanoparticles, even though both accumulated to a similar extent within the tumor microenvironment.

4. Compartmental Model Analysis of Tumor Localization and Uptake

Compartmental modeling provides insights into the impact that tumor-specific targeting can have on the tumor localization of systemically applied therapeutics. Targeting ligands that can enhance tumor-specific binding (k23) are not expected to increase overall tumor uptake (C2+C3) for entities that remain trapped in the tumor microenvironment and do not reversibly return to the blood circulation. But simulations also show that for entities that can rapidly exchange between the blood compartment and the tumor interstitial space, tumor-specific targeting can significantly improve tumor uptake.

This study highlights the potentially important difference in the relative distribution between intracellular and extracellular tumor space for targeted and nontargeted entities. Nonspecific tumor accumulation can dominate for sufficiently large macromolecular entities, whereas specific interaction between targeting ligands and tumor cells can drive tumor accumulation for relatively small molecules. Besides, the physicochemical properties of nanoparticle carriers will largely determine their pharmacokinetics/biodistribution, but the presence of targeting ligands can greatly enhance intracellular uptake. This study also suggests that the optimization of internalization may be key for the development of effective nanoparticle-based targeted therapeutics.

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United Kingdom