The Challenges Facing Cancer Nanomedicine
Almost 30 years later, can researchers overcome the limitations of cancer nanomedicine and realize its potential?
The first cancer nanomedicine was approved by the U.S. FDA almost 30 years ago. Despite the promise of this invention and extensive research efforts, only 13 additional cancer nanomedicines have been approved since then. While there are still many challenges that must be overcome, scientists persist in working toward a targeted cancer nanomedicine that can outperform existing therapies.
What is nanomedicine?
Nanomedicine treats health conditions using particles 1 to 100 nm in size that consist of a carrier encapsulating or conjugated with a therapeutic agent.1 This technology exists on the same scale as many other biologically relevant molecules such as antibodies, proteins, and enzymes.
What is the primary goal of nanomedicine?
With the right design, nanomedicine could deliver personalized therapeutics to specific cells or tissues of interest. This innovation has the potential to improve the efficacy, bioavailability, dose response, and safety of therapeutics compared to conventional medicines.
How does cancer nanomedicine work?
Cancer nanomedicine uses nanoparticles encompassing therapeutic agents like chemotherapies to target tumors. Unlike systemic chemotherapy, cancer nanomedicine can more precisely target cancer cells, preventing side effects like nausea and hair loss and improving patient compliance with treatment regimens.2
The principles of cancer nanomedicine rely on the enhanced permeability and retention (EPR) effect, first described in 1986 by Masumura and Maeda.3 In this phenomenon, leaky vessels that supply blood to the tumor allow particles up to hundreds of nanometers in size to extravasate into the tumor. At the same time, the lowered lymphatic drainage within the tumor facilitates the accumulation of these particles.
"Only 14 systemically administered cancer nanomedicines have been approved for clinical use worldwide."
The first nanomedicine
The EPR effect was first demonstrated in studies of Doxil, which became the first FDA-approved nanomedicine in 1995.4 Doxil was designed to improve the clinical utility of Doxorubicin, a chemotherapy used to treat malignancies such as breast and ovarian cancer. While Doxorubicin effectively destroys tumor cells, it also affects the heart and kidneys.
Researchers were searching for a way to prevent the off-target effects of Doxorubicin and turned to nanomedicine.5 The solution was to encapsulate this chemotherapy in a liposomal enclosure, allowing its preferential delivery to tumors based on the EPR effect. The resulting therapeutic, Doxil, accumulated in high levels around the tumor as expected without affecting the heart or kidneys, unlike free Doxorubicin.
What are the challenges of cancer nanomedicine?
Despite the excitement around this treatment area and ongoing research efforts, only 14 systemically administered cancer nanomedicines have been approved for clinical use worldwide. Most of these nanomedicines are like Doxil and are liposomal formulations of existing small-drug chemotherapies.
While these nanomedicines limit the negative side effects associated with chemotherapy, only a few of them show enhanced therapeutic efficacy over their free version. This is likely because an average of 0.7 percent of the nanoparticles systemically injected in animal models accumulate at the tumor site.6
One of the major challenges threatening the success of this field is the lack of knowledge of how nanomedicines interact with the body.7
Upon entering the circulation, blood proteins can bind to nanoparticles, forming a corona that alters their physiochemical properties and how they interact with the tumor microenvironment. These nanoparticles can also be sequestered by macrophages and endothelial cells in the spleen and liver before reaching the tumor.
Another challenge is that the EPR effect can vary greatly between tumors, making it difficult to predict therapeutic efficacy.
One solution to these challenges is active targeting.
Active targeting: the gold standard of cancer nanomedicine
Active targeting has long been the goal of cancer nanomedicine—the ability to deliver therapeutics specifically to tumor cells without relying on the EPR effect.
Researchers are adding affinity ligands to the surface of nanoparticles to increase their specificity and limit their uptake to diseased cells.8 The ligands are chosen based on the unique molecular characteristics of each tumor. Engineering these nanoparticles can be complex because of how surface moieties could affect their interactions with the body.
While many clinical trials are underway, no targeted nanomedicine has shown sufficient efficacy to warrant its approval.
"The ideal scenario would be to have a specific nanomedicine that can home in on tumors while eliminating all cancer cells."
This is because of two main challenges.9 The first is that nanoparticles need to be within the vicinity of the tumor in order to act on the cancer cells, meaning that this type of nanomedicine is still reliant on the EPR effect. The second is that targeting cancer cells with only one ligand could leave malignant cells behind. It can also be difficult for these cells to penetrate deeper within the tumors.
The ideal scenario would be to have a specific nanomedicine that can home in on tumors while eliminating all cancer cells.
One of the potential solutions to these challenges is to use cells as the vessel for delivering targeted therapeutics. Some cell types, such as immune cells, are equipped with onboard sensing that allows them to follow signals to tumors.10
For example, neutrophils migrate to the sites of inflammation in response to chemokine signals secreted by cancer cells. Macrophages are also found in the tumor microenvironment and home to tumors in response to chemoattractant signals.
The idea would be to create a therapeutic “trojan horse” where the treatment is loaded into immune cells and shuttled into tumors for targeted delivery.
How can we improve cancer nanomedicines?
Researchers are exploring many other ways to improve cancer nanomedicine and realize the potential this area holds.2
One idea is to use this nanomedicine to deliver immunotherapy that would increase the efficacy of immune targeting in the tumor microenvironment. Controlled release mechanisms are also being added to prevent the early distribution of therapeutics in the body. For this approach, characteristics that are unique to the tumor microenvironment such as acidity could be used to trigger the release of the therapeutic.
Finally, scientists are working to pack more than one chemotherapy into nanoparticles to deliver combination therapies that eliminate all cancer cells and prevent recurrence.
For this work to be productive, researchers need to develop accurate preclinical models of the tumor microenvironment in humans that will improve the translation challenges that have been plaguing the field of cancer nanomedicine.
