Nanotechnology Provides “Rocket Launchers”and “Magic Bullets” as Anticancer Weapons

Although tremendous growth and success have been seen in the realm of oncology during the last decade, cancer remains a commonly fatal malady that accounts for millions of global deaths annually. It was reported that 9.6 million people died from cancer in 2018 and the number of cancer-related deaths would be increased up to approximately 30 million a year by 2030 (CA, 2018; The Lancet, 2018). 

Limitations of Conventional Therapies

Current clinically prevailing treatments for cancer rely on surgery, radiation and chemotherapy, which are all seriously dissatisfactory due to their limited therapeutic potential. Specifically, surgery and radiation can be applied only in certain circumstances where tumor cells can be seen on imaging scans to avoid damaging to healthy tissues. Chemotherapy, as a current mainstay cancer treatment, has been extensively exploited in clinic thanks to its inherent simpleness and convenience. However, the problem consists in its low efficiency in drug delivery, nonspecific drug distribution and associated underlying side effects such as hair loss, weakness and immune-depression as the chemical agents could be toxic to normal cells as well as malignant tumors. Innovative strategies are urgently demanded to break through those limitations of current methods and achieve more efficient and radical cure for cancer.

Cancer Nanotechnology Coming to the Rescue

Recently, researchers are putting a lot of effort in creating drugs exploiting nanotechnology, which involves the control of extremely tiny biological particles such as atoms and molecules, to create new materials with a variety of functional properties, including many that could be exceptionally beneficial for cancer treatment. The first cancer nanomedicine, Doxil, was approved by the U.S. Food and Drug Administration (FDA) in 1995, since then a dramatically growing number of nanoparticles have been reported as drug carriers or therapeutic agents, capable of performing early diagnosis, curing with minimal side effects, and evaluating the efficacy of the treatments in a non-invasive way, etc.

Nanotechnology in Cancer Treatment

Nano Rocket Launchers: Nanoparticles as Drug Carriers

Some novel chemotherapeutic agents such as calcium phosphate and citrate have been under investigation for a few years. Unlike indiscriminate attacks seen from typical agents in traditional chemotherapeutics, calcium phosphate and citrate only kill cancerous cells they are delivered into, thus avoiding off-tumor toxicity. Nevertheless, calcium phosphate and citrate are also involved in the regulation of many cellular signaling pathways. So here comes the pivotal problem: how to transport them into targeted cancer cells without disrupting normal cellular signals? 

A solution from nanotechnology was reported last month. Researchers from Ludwig Maximilian University of Munich encapsulated calcium phosphate and citrate in a lipid layer, creating nanoparticles capable of bypassing regulatory controls (Chem, 2020). Those nanoparticles remained intact until they were taken up by cancer cells where the lipid layer was broken down and large amounts of calcium and citrate inside were released into the cytoplasm.  Notably, a second membrane coat was observed covering those nanoparticles before cell uptake. The membrane was exclusively ruptured in cancer cells and allowed compounds leaking only there rather than in healthy ones, giving a highly selective toxicity to the nanoparticles. 

However, the underlying molecular mechanisms behind this selective rupture remain unknown and demand further exploration.

The lipid-based nanoparticle enters into and releases toxic compounds in a cancer cell. (Credit: Constantin von Schirnding, et al.)

The vast majority of work to date in the realm of cancer nanotechnology has focused on spherical liposomes as those involved in the previously mentioned study, however, an increasing number of inorganic materials (such as silica) has also been seen to be used for drug delivery in recent years. For instance, researchers from Houston Methodist Research Institute once used tiny silica beads to precisely transport chemotherapy drugs into fibroblasts surrounding and nourishing cancer cells, showing the potential of silica nanoparticles in improving drug delivery with reduced side effects (NIH Director’s Blog, 2014).

Nanospheres are being swallowed up by human fibroblasts surrounding cancer cells.
 (NIH Director’s Blog, 2014)

Moreover, porous nanoparticles have gained great attention from cancer nanotechnology researchers toward designing controlled drug delivery systems because of their remarkable properties, including low toxicity, high physico-chemical stability and capacity for loading various types of agents. A combination of porous nanoparticles and lipid bilayers was also designed to simultaneously transfer diagnostic agents and therapeutic drugs for both diagnosis and therapeutic applications. This combinatorial design can lead to the death of a drug-resistant human hepatocellular carcinoma cell, showing a 106-fold improvement over comparable liposomes as reported in Natural Material (Natural Materials, 2011).

Magic Nano Bullets: Nanoparticles as Therapeutic Agents

Instead of serving as drug-delivery vectors, some nanomaterials have also been designed to directly kill cancer cells without loading any extra therapeutic compounds. Magnesium silicide nanoparticles, one type of reported self-therapeutic nanomaterials, can act as deoxygenation agents, depriving the tumor of oxygen needed for growth and significantly inhibiting tumor proliferation in a mouse model (NN, 2017). The mechanism of action can be explained by the following chemical reactions:

Another strategy to take advantage of both chemistry and nanotechnology for cancer therapy is to convert H2O2 into highly toxic hydroxyl free radicals (OH·) to kill cancer cells. In this scenario, researchers have synthesized different nanomaterials based on gold, silver, iron and so on to combat cancer (ANM, 2020).

The Nobel laureate Paul Ehrlich once described site-specific drugs as “magic bullets”, because they are capable of killing specific microbes while leaving the rest of body essentially unscathed (NRC, 2008). In a similar context, boron-based nanosphere can be viewed as one of “magic nano bullets”. In a study published in 2014, investigators synthesized hollow boron nitride nanospheres and examined their in vivo anticancer effectiveness in subcutaneously and orthotopically injected human prostate adenocarcinoma cells mouse models. The results indicated that those boron nitride nanospheres significantly suppressed prostate cancer cell proliferation while no obvious hepatic or renal toxicity observed in treated mice (Nature Communications, 2017). The mechanism of their anticancer performances may lie beneath the inhibitory ability of their hydrolysed form, boric acid, which can reduce intracellular calcium signals and calcium storage in cancer cells, thus restraining tumor growth.

Concerns and Future of Cancer Nanotechnology

Although nanotechnology has been extensively applied in cancer diagnosis and treatment due to its capability of improved efficacy in drug delivery and selective cancer toxicity, there are growing safety concerns over potential nanoparticle-triggered diseases. For instance, scientists have known for more than a decade that some nanoparticles migrating to the lungs would cause acute lung injury in vivo. In an article published in 2009, researchers showed that several types of nanoparticles would trigger autophagic cell death in lung through a certain signaling pathway (Journal of Molecular Cell Biology, 2009). Autophagy, as a normal process of cell growth and renewal cycle, degrades damaged materials in a cell. Nonetheless, an overactivity of this destruction process was reported to result in cell death. Besides, the small size, high reactivity, and unique tensile and magnetic properties of nanomaterials have also raised concerns about their implications for the environment.

Despite those concerns related to cancer nanotechnology, remarkable progress addressing paramount problems in cancer care and treatment has been made in this filed through multidisciplinary investigations bringing together physicists, chemists, and engineers working with clinicians and biologists, making the impossible possible. Maybe one day, we will see the creation of implantable nano devices capable of automatically detecting cancer cells, treating them and reporting to the doctor from inside the body, just as the scene you may see from a science fiction movie.

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