In vivo assembly of nanoparticle components to improve targeted cancer imaging

Abstract

Many small molecular anticancer agents are often ineffective at detecting or treating cancer due to their poor pharmacokinetics. Using nanoparticles as carriers can improve this because their large size reduces clearance and improves retention within tumors, but it also slows their rate of transfer from circulation into the tumor interstitium. Here, we demonstrate an alternative strategy whereby a molecular contrast agent and engineered nanoparticle undergo in vivo molecular assembly within tumors, combining the rapid influx of the smaller and high retention of the larger component. This strategy provided rapid tumor accumulation of a fluorescent contrast agent, 16-and 8-fold faster than fluorescently labeled macromolecule or nanoparticle controls achieved. Diagnostic sensitivity was 3.0 times that of a passively targeting nanoparticle, and this improvement was achieved 3 h after injection. The advantage of the in vivo assembly approach for targeting is rapid accumulation of small molecular agents in tumors, shorter circulation time requirements, possible systemic clearance while maintaining imaging sensitivity in the tumor, and nanoparticle anchors in tumors can be utilized to alter the pharmacokinetics of contrast agents, therapeutics, and other nanoparticles. This study demonstrates molecular assembly of nanoparticles within tumors, and provides a new basis for the future design of nanomaterials for medical applications. Determining the correct prognosis and therapeutic options for cancer requires accurate staging and surveillance of tumors. Current detection strategies typically combine sensitive imaging modalities with contrast agents (1, 2). Yet these approaches fail to detect lesions in many cases, typically because poor imaging contrast is achieved (2). This can be improved through tumor targeting strategies that link contrast agents to a polymer or nanoparticle. Nanoparticles are well suited to act as tumor targeting vehicles because their in vivo behavior is determined by their design, and they are able to leak into and accumulate in tumors via the enhanced permeability and retention effect (3-7). Despite these advantages, several obstacles limit effective tumor detection with nanoparticle-based targeting strategies. Passive targeting requires particles with large diameters, but this simultaneously restricts transport into tumors and accumulation occurs only after many hours in circulation (8-10). Actively targeting nanoparticle designs can achieve faster accumulation (11-13), but may not be appropriate for detecting lesions whose antigens are uncharacterized or are heterogeneous and therefore unreliable. Finally, nanoparticles have long circulation and persistence times in the body, raising potential concerns of diagnostic or therapeutic agent toxicity. It would therefore be advantageous to develop targeting strategies that can rapidly accumulate contrast agent into tumors without relying on antigen characterization and without causing long-term persistence in the body.The movement of nanoparticles th...

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