The age of theranostic nanoparticles

Over the past several years, theranostic nanoparticle studies have provided several shining examples of where molecular cancer imaging is going. In this review published ahead of print Nov. 20 in the Journal of Nuclear Medicine, researchers discuss the triumphs and tribulations of these tiny yet potent structures.

Theranostic nanoparticles have to do several things to be successful. Firstly, they have to be not only biocompatible, but biodegradable in order to be safe for human use. They need to accumulate quickly and bind to their targets and allow for the documentation of essential information regarding biochemistry, pathology and morphology without creating collateral damage and then leave the body like a hiker leaving the woods—ideally leaving no signs they were ever there. It’s a tall order and so far not one single theranostic nanoparticle has been perfect on all fronts. 

Feng Chen, PhD, and Emily B. Ehlerding from the Cai Research Group led by Weibo Cai, PhD, at the University of Wisconsin–Madison made an assessment of how far theranostic nanoparticles have come and the challenges that remain.

“Efficient targeting of theranostic nanoparticles to the tumor site is critical for both diagnosis and therapy. However, difficulties still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor-targeting capabilities,” wrote Chen et al.

To be approved or not approved
The FDA has approved more than 35 nanoparticle-based agents, either for imaging or therapeutic purposes, to be used in clinical trials. However theranostic nanoparticles, those that are multifunctional and combine imaging and therapy capabilities in one shot, are still in their infancy and so far none have been approved in this capacity. Therefore, this research remains preclinical until such time that their efficacy can be proven for humans.

“The engineering of theranostic nanoparticles using FDA–approved imaging or therapeutic nanoplatforms may be a viable option,” the researchers explained.

Quantum dots, gold nanostructures and iron oxide nanoparticles can all be conjugated with targeted therapies and diagnostic agents. Such structures can also be tagged using fluorescent dyes and other optical or magnetic agents; and cage or many-chambered nanoparticles such as porous silica, ferritin and polymeric nanoparticles can encase various theranostic agents. Researchers have now gone a step further to engineer nanoparticles that have built-in imaging and therapeutic characteristics, such as Cu-64 copper sulfide CuS, porphysomes, and gold “nanoshells.”

These already finely engineered structures are further enhanced with polyethylene glycol and other materials to improve tumor targeting and circulation in the blood.

Targeting and circulation
The first generation of nanoparticles relied on tumor retention and permeability to help it do its work, but tumor heterogeneity complicates this simple design. Thankfully, targeted theranostics can home in on specific overexpression of receptors and other targets to help nanoparticles find their way. One such mechanism is angiogenesis, or the targeting of newly developing vasculature in and around advancing tumors.

Peptide-modified ferritin nanocages can be leveraged to target integrin avb3, a biomarker of tumor proliferation. These nanocages are made of protein in 24 tiny units that are “self-assembled” into cages. When filled with photosensitizers and radioisotopes, these have been shown to be effective in preliminary research imaging and treating integrin avb3 active tumors. A few of these include cages dosed with ZnF16Pc, copper-precomplexed doxorubicin and ZW800 near-infrared dye and hybrid BaYbF(5) nanoparticles. The major limitation with these has been the possibility of heavy metal toxicity.

Targeting folate receptors is another option, and researchers have taken advantage of this with trigger-activated nanobeacons made possible with folate-conjugated porphysomes. Heparin–folic acid–IR-780 nanoparticles, and specialized iron oxide nanoparticles also can be used to target folate receptors.

Theranostic particles combined with prostate specific membrane antigen (PSMA) compounds is an emerging area, as well as those that bind to the urokinase plasminogen activator receptor in the case of pancreatic cancer. “Smart drugs” that can be activated in real-time during imaging and therapy like the porphysome nanobeacons appear to be the next generation of these drugs, but when and how these will be translated to clinical practice remains to be seen. The use of PET to evaluate up-and-coming theranostic nanoparticles will be an important strategy.

“Clearly, there is a trend toward combining the diagnostic and therapeutic functions of theranostic nanoparticles, resulting in greatly improved personalized disease management,” the authors wrote. “For clinical translation to take place, many major challenges must be overcome, such as selection of the best nanoplatform, improvement of ligand conjugation efficiency, and development of an ideal synthetic technique with fewer steps, higher reproducibility, and lower cost.”