Over the past several years, studies involving theranostic nanoparticles have provided several shining examples of where molecular cancer imaging is going. Health Imaging discussed the future of theranostic nanomedicine with Weibo Cai, PhD, the head of the research lab at the University of Wisconsin–Madison, where Cai’s team has taken full inventory of all the triumphs and tribulations of these tiny yet potent structures.
Theranostic nanoparticles have to do several things to be successful. Not only do they have to be biocompatible, but also biodegradable in order to be safe for human use. They need to accumulate quickly, 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 of ever being there. It’s a tall order and, so far, not one single theranostic nanoparticle has been perfect on all fronts.
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 none have been approved in this capacity for humans.
“Generally, organic and polymeric nanoparticles with high biocompatibility and biodegradability hold greater chances for future clinical translation,” explains Cai. “Most of the inorganic nanoparticles with attractive drug delivery, optical, magnetic or photothermal properties are still struggling to advance into clinical trials due to potential toxicity concerns. However, progress has been made during the last decade. For example, inorganic nanoparticles, such as superparamagnetic iron oxide nanoparticles, gold nanoshells, ultra-small silica nanoparticles, or Cornell dots, are currently either being used for clinical disease diagnosis or under active clinical trials.”
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 the gold nanoshells, Cai notes. These already finely engineered structures are further enhanced with polyethylene glycol and other materials to improve their performance once inside the body.
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 used 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 that looks into 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.
“Translational research of nanoparticles, especially inorganic nanoparticles, will continue to be one of the major challenges in the field of cancer nanomedicine,” says Cai. “Encouragingly, over the past two decades, over 35 imaging or therapeutic nanoparticles have been approved by the FDA for clinical trials. To alleviate the potential long-term toxicity, we believe biodegradable or renal clearable nanoparticles with attractive diagnostic and/or therapeutic capabilities might have a better chance for future clinical translation.”
Targeting folate receptors is another option, and researchers have taken advantage of this with trigger-activated nanobeacons