A Fantastic Voyage Through a Nano-Sized Universe

The 1960s was the birthplace of many tumultuous events, of which the Vietnam War, civil rights movement, and Kennedy assassination were a few. A more obscure, somewhat smaller event, however, was the making of the sci-fi movie Fantastic Voyage. Born from the political upheaval of the Cold War, the movie was a fantastic popularization of futuristic medicine: the idea of a doctor and his team, shrinking to the size of a microbe, flying through a patient’s bloodstream to save his life (1).

While most definitely controversial and extremely far-fetched, this idea of a miniaturized doctor swimming through the body has intrigued science for quite some time. A few years before Fantastic Voyage hit film, the great physicist Richard Feynman had already begun to play with this idea of a tiny doctor. In his 1959 lecture at Caltech, he presented the idea of “swallowing the doctor” – essentially building a tiny, ingestible robot to perform surgery on hard-to-reach parts of the body (2).

Although he approached this from a quantum physics standpoint, Feynman facilitated a launching point for nanotechnology, and in particular, the area of nanomedicine. The idea of a tiny, functionalized material was captivating to think about. What if you could build a microscopic machine to achieve a function on its own? What if human control and direction were no longer needed? What if this machine, no longer needing any sort of stimulation, could think and act on its own, regardless of the roadblocks thrown in its way?

Although we are far from answering those questions, nanotechnology has brought us closer than ever to building a truly functionalized nanomaterial. Nanoparticles – tiny, minute particles – are the bridge from bulk materials to atomic and molecular structures. Ranging from one to 100 nanometers in size (A human hair is about 100,000 nanometers in diameter), nanoparticles are currently being scrutinized, manipulated, and prodded in hundreds of labs across the country. Found as far back as 4th century Rome, they range from naturally derived materials such as polymers and carbons, to chemically synthesized compounds such as metal oxides (3).

The hydrophilic and/or hydrophobic nature of the nanoparticle has allowed great advancement in the field of disease therapeutics. Nanoparticles are much more suited for drug delivery than free drug techniques, shown through enhanced tumor accumulations, reduced system exposure, and decreased side effects. Nanoparticles also have a long circulation half-life, making it easier and more convenient to locate a particular tumor or diseased site (4).

One interesting point for nanoparticle engineering is the fact that they can be covered in different cell membranes. A promising technique is to encase the nanoparticle in a red blood cell (RBC) membrane, so that the cells of the immune system will not be able to recognize the nanoparticle as a foreign substance to attack (5). These nanoparticles can be engineered to have a triggered release when in contact with a specific substance or can circulate freely throughout the body completely unrecognized by bodily cells. Due to their biocompatibility and biodegradability, they will have no toxic effects on the body. Moreover, they can be synthesized to degrade after delivering a drug molecule, or after a certain time point (5).

The world of personalized medicine can also be applied to RBC membraned coated nanoparticles. Blood drawn from a patient can be used to coat nanoparticles, thus creating a patient specific nanoparticle coating. Furthermore, transfusions from blood banks can be used to coat nanoparticles in specific blood types, allowing for universal coating materials through blood matching and O-type blood (6). On average, there are around one billion RBCs in 1 mL of human blood. This provides an abundance of coating materials for a plethora of nanoparticles. Furthermore, this patient-specific technique would maximize immune tolerance and minimize immune system interference (6).

Red blood cells were the first type of cell to be sacrificed as clothing for their newly disguised nano-counterparts. In the few years since then, the membranes of cells such as platelets, white blood cells, and even cancer/bacteria cells have become cloaking mechanisms for nanoparticles. Platelets, other than providing a mechanism to maintain hemostasis, were found to attract bacteria. Coating nanoparticles with platelet membranes was shown to increase antibiotic delivery to eliminate bacteria, in a controlled and localized fashion (5). White blood cells, in particular, showcase site-specific targeting towards tumors, providing a fail-safe method towards cancer drug delivery as opposed to a circulation dependent chemotherapy. This targeted cancer treatment has been seen again in cancer cell membrane coated nanoparticles. In a somewhat suicidal move, cancer cells have been shown to “self-target” – accumulating with other cancer cells at the main tumor site. As the nanoparticles are disguised as cancer cells, this “self-targeting” acts a GPS locator to deliver the nanoparticles in their stealthily coated state to the tumor site for targeted cancer drug delivery.7

Nanoparticles are also small and stealthy enough to penetrate and manipulate cancer cells. A common technique to treat cancers is through the usage of nanoparticles containing antibodies, drugs, vaccines, or metallic particles. These nanoparticles can be loaded with multiple drugs for combination therapy, which is known to suppress cancer chemoresistance (cancer cells resisting a singular chemotherapic drug) (8). The enhanced permeability and retention effect, known as EPR, allows for enhanced accumulation in tumors, while decreasing accumulation in healthy organs. This creates pores on the tumor surface in sizes ranging from 200 nm to 2 μm (human hair is about 100 μm or 100,000 nm), a pore size suited for nanoparticles to travel through into the tumor. The lack of drainage system prevents the nanoparticles from travelling out of the tumor, which also aids in nanoparticle accumulation. This effect is not present in healthy organs, because a protective lining of tightly packed endothelial cells prevents migration of the nanoparticles into healthy tissues (9).

An older technique of nanoparticle cancer treatment is to expose metal-coated nanoparticles to magnetic energy, infrared light, or radio waves, causing heat radiation. Exposure to heat causes nanoparticles’ magnetic orientation to oscillate wildly, absorbing electromagnetic energy and converting it into thermal energy (10). The idea of using heat to treat cancer was first exploited in Ancient Egypt, Greece, and Rome, where heat was used to treat breast cancer masses. In Greece, Hippocrates, known as the Father of Medicine, reported successfully treating breast cancer using heat. In fact, he coined the phrase, “What medicines to not heal, the lance will; what the lance does not heal, fire will” (11).

Heat can kill cancer cells, and with a bit of manipulation also has the ability to awaken the body’s immune system. First, an inactive nanoparticle is coated with a metal such as gold, iron, or silver. Once in the body, the nanoparticle can be activated by a light or energy source. The metallic coating will naturally give off heat externally, which can kill a portion of the malignant cells. By manipulating the heat, the immune system can be alerted to the presence of the cancer cells, thus identifying and killing the cancer cells not affected by the heat (12). This technique reverses and essentially demolishes the cancer cell’s primary offensive/defensive methodology, in which it tricks the immune system into believing everything is normal while the cancer cells multiply, take over, and destroy the body (12).

Nanoparticles display a wide range of possibilities, in which the treatment solution is reached with marginal harm to the healthy parts of the body. They display great promise as a novel, biologically relevant and biocompatible approach as an effective drug delivery platform – and also as functionalized vehicles for disease treatment.

With this great advancement in technology, revisiting some earlier questions may bring these innovations into a shadier perspective. Currently, the FDA has mainly approved liposomal or polymeric nanoparticle treatments – essentially limiting the scope of clinically applied nanomedicine to passive, biologically friendly compounds that are less unique treatments than additives to pre-existing drug molecules (13). The advantages of these treatments are characteristic of nanoparticle technologies in general: longer circulation, increased drug delivery for site specific targeting, lower systemic toxicity, and controlled or localized delivery (14). Beyond the area of treatment, however, metallic and inorganic nanoparticles have been utilized as imaging or ultrasound agents and have been applied for thermal cancer therapy (15).

Gene therapy in connection to nanotherapeutics, however, is an interesting cross-disciplinary area that has just now begun to enter the clinical stage. Nanoparticles provide a highly compatible carrier for genes; varying the surface charge on the nanoparticle allows for extremely stable interactions between the gene and the vesicle, while also increasing circulation time and protecting the internal contents from degradation (16). Although extremely promising, the issues that this technology faces are not limited to the original problems of gene therapy itself (such as immune system mediated inflammation or lack of specificity) (17). Now, through combining nanotechnology with gene therapy, issues from both technologies have arisen to complicate future application. Nanoparticles tend to aggregate and are occasionally absorbed by nonspecific tissues. This lack of targeting ability provides danger towards wrongful gene delivery, and subsequent uptake by the cell. Furthermore, immune system recognition of the delivery system is still a major problem, leading to adverse side effects and toxic byproducts (17).

Quite recently, an attempt to functionalize nanocarriers was made through a centuries old paper game – origami. Scientists began by building a nanorobot using DNA. Because DNA has an inherent ability to form self-assembled structures, this allowed for thrombin (a clotting agent) to be released for cancer cell elimination. The DNA formed a nanotube, like a Pixie Stix – entrapping the thrombin within its folds. Upon exposure to the tumor marker nucleolin, unfolding occurs, allowing for subsequent drug release and tumor eradication. As demonstrated in small pigs, release of the clotting agent occurred specifically at the tumor sites, with little to no effect towards other organ systems. Furthermore, liver uptake of the nanotube did not show extreme toxicity, and the nanotubes were successfully cleared or degraded (18).

Functionalized nanocarrier delivery systems have yet to be approved by the FDA and have yet to become a staple in modern disease treatment. Although recent advances have been both successful and exciting in their scope and impact, considering the course of this research moving forward leads to questions about how small we can go. Without knowledge of nanoparticle whereabouts, it is difficult to fully track the pathway of treatment throughout the body. While metallic particles can be traced through photoacoustic and magnetic resonance/computer tomography techniques, non-metallic particles cannot be visualized in a non-invasive way unless coupled with a fluorescent tracker (19–20).  And despite the miraculously tiny size of these nanoparticles, immune system recognition can lead to greater problems than the original disease (21).

Fantastic Voyage, though highly fictionalized, highlights the unexpected problems a small vehicle can face while racing through the body. The crew of doctors takes a detour through the heart (inducing a small cardiac arrest to avoid turbulence), passes through the lungs to regain oxygen, and travels through the inner ear (while pleading for outside silence to minimize turbulence) (1). Although the resulting six-minute operation is successful and the crew escapes to normality shortly after, this movie provides insight into truly how wondrous and complex the human body really is. It is often unknown how the body will react to something so tiny and foreign disrupting activity. If the tiny and foreign object can react to the body’s actions, a chain of negative side effects can occur – much like a line of dominos falling over one another.

Although the future of functionalized nanotechnology is as bright as the metallic nanoparticles heralding it, this juxtaposition between size, intelligence, and feasibility is something that must be carefully considered. Tricking Mother Nature often has unintended consequences – no matter how tiny the vehicle.

Maggie Chen is a first year in Wigglesworth

Works Cited

[1] IMDB. https://www.imdb.com/title/tt0060397/ (accessed Sept. 26, 2018).

[2] Feynman, R. There’s Plenty of Room at the Bottom. December 29, 1959.

https://www.zyvex.com/nanotech/feynman.html (accessed Sept. 26, 2018).

[3] Krukmeyer M.G. et al. J Nanomed Nanotechnol. 2015, 6, 1-7.

[4] Blanco E. et al. Nature Biotech. 2015, 33, 941-951.

[5] Fang F. et al. Adv. Mater. 2018, 30, 1-34.

[6] Hu C. M. J. et al. PNAS. 2011, 108, 10980-10985.

[7] Li R. et al. APSB. 2018, 8, 14-22.

[8] Swain S. et al. Curr. Drug Deliv. 2016, 13, 1290-1302.

[9] Wang M. et al. Pharma. Research. 2010, 62, 90-99.

[10] Jain S. et al. Br. J. Radiol. 2012, 85, 101-113.

[11] DeNardo G. L. et al. Cancer Biotherm. Radiopharm. 2008, 23, 671-679.

[12] Fekrazad R. et al. J. Lasers Med. Sci. 2016, 7, 62-75.

[13] Bobo D. et al. Pharma. Research. 2016, 33, 2373-2387.

[14] Anselmo A. et al. Bioeng. & Trans. Med. 2016, 1, 10-29.

[15] Parvanian S. et al. Sen. And Bio Sens. Research. 2017, 13, 81-87.

[16] Rosenblum D. et al. Nat. Comm. 2018, 9, 1-12.

[17] Chen J. et al. Mol. Therapy. 2016, 3, 1-8.

[18] Li S. et al. Nat. Biotech. 2018, 36, 258-264.

[19] Meir R. et al. Nanomed. 2014, 9, 2059-69.

[20] Lee J. M. et al. Mol. Therapy. 2012, 20, 1434-42.

[21] Shi J. et al. Nat. Rev. Cancer. 2017, 17, 20-37.

Image credit: Wikimedia commons

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