Passive Targeting in Nanomedicine
How nanoparticles find their way to tumors without being steered there, why so few of them arrive, and why this approach still underpins every approved cancer nanomedicine.
In brief
Publication: this page summarizes our chapter, "Passive targeting in nanomedicine: fundamental concepts, body interactions, and clinical potential," in Nanoparticles for Biomedical Applications (Elsevier).
Key point: passive targeting relies on leaky tumor blood vessels rather than molecules that seek out cancer cells. It delivers only a small fraction of nanoparticles to tumors, yet every FDA-approved cancer nanomedicine at the time of writing was built on it.
The delivery problem
Nanoparticles, engineered materials roughly 1 to 100 nanometers across, can carry drugs or imaging agents through the bloodstream. For most nanomedicines to work, they need to reach diseased tissue and avoid healthy organs. That journey is difficult: as soon as nanoparticles enter the blood, proteins coat their surface, forming a "protein corona," and immune cells in the liver and spleen clear many of them away before they reach a tumor.
Active versus passive targeting
Researchers use two broad strategies. Active targeting coats nanoparticles with ligands, such as antibodies or peptides, designed to bind receptors on cancer cells. Passive targeting relies instead on the abnormal biology of tumors. Both depend on the same first step: nanoparticles slipping out of tumor blood vessels through gaps between the cells that line them.
How passive targeting works
Passive targeting rests on the enhanced permeability and retention (EPR) effect, first described in 1986. Fast-growing tumors build chaotic, leaky blood vessels with gaps that can range from a few to several hundred nanometers. Nanoparticles small enough to fit through those gaps can diffuse into the tumor, and because tumors drain fluid poorly through their compressed lymphatic vessels, the particles tend to stay there. The design rules follow from this: make nanoparticles smaller than the gaps, and keep them circulating in the blood long enough to have a chance to cross.
The limits
- Low delivery. A meta-analysis of preclinical studies found that only about 1% of an injected nanoparticle dose reaches a solid tumor, and far less reaches the cancer cells themselves. Most particles end up in the liver and spleen.
- Variable tumors. The EPR effect differs between tumors, between patients, and even within a single tumor, which leads to uneven drug distribution.
- Mice aren't people. The effect was observed mainly in mouse models, and how strongly it occurs in human tumors is still debated.
Shaping how nanoparticles interact with the body
Design choices can change a nanoparticle's fate. Coating it with polyethylene glycol (PEG) reduces protein buildup on its surface, helping it circulate longer and avoid immune clearance. The chapter also covers how nanoparticles interact with the blood, with immune cells in the liver and spleen, and with the kidneys.
Clinical potential
Despite more than 1,500 preclinical papers on active targeting, every FDA-approved cancer nanotherapeutic at the time relied on passive targeting, starting with Doxil, a PEG-coated liposome carrying the chemotherapy drug doxorubicin, approved in 1995. Many were approved for having fewer side effects than the free drug rather than for improving survival. Looking ahead, the chapter points to better animal models, imaging to identify which patients are likely to benefit, and nanoparticles tailored to an individual's cancer.