Nanoparticles: small particles; big potential

By Meng Lou

The apple has classically served as an embodiment of health and prosperity. Many wonder why the Greek Goddesses Hera, Athena, and Aphrodite fought so tenaciously over such a token? However, where there is a virtue there is also a deceptive counterpart, for the apple has been implemented just as many times in negative light. In the classical Snow White, the villain gifts a poisonous apple to kill the protagonist. Despite this, there is some truth to the “poisonous apple” metaphor. Its shiny red exterior is matched only by the sweetness of the fruit, tempting and deceptive by nature. The seeds, however, contain traces of cyanide. When consumed in excess, they can be lethal. The apple represents an interesting scenario-dependent duality in the context of the divine, it represents health; of villains, deadly poison. Nanoparticles, miniscule particles, invisible to the naked eye and capable of delivering cargo to cells in the body, mimic this double-edged nature, bringing us a step closer to a potential treatment to cancer.

Cancer, simply defined, is an uncontrolled growth of cells; canonically, a manifestation of a multitude of hallmarks ranging from angiogenesis to upregulation of growth factors, to suppression of programmed cell death [1]. In all its complexity, cancer is ultimately one thing: a self-perpetuating problem. With the ability to not only divert large amounts of resources and expand its population, cancer presents a further degree of spontaneity with its capacity to migrate and metastasize to a new location [1]. Difficulties in treatment of cancer surgically stem from its mobility, contributing to the high frequency of relapses. New methods have been employed to fight the war against cancer that has plagued humanity for generations—methods that now begin to match the complexity of cancer cells themselves. Among the promising candidates of cancer treatment are Bi-specific T-cell Engagers (BITE), which physically bring activated killer T-cells within cancer cell proximity to take advantage of T-cell cytotoxic behaviors. Additionally, chimeric antigen receptor T-cell therapy (CARs) is an approach that programs T-cells isolated from one’s blood to recognize and target cancer for a more personalized, living cancer therapeutic [2, 3]. With recent developments in chemistry and chemical engineering, manipulation and synthesis of nanoparticles may provide a new paradigm in cancer treatment.

“New methods have been employed to fight the war against cancer that has plagued humanity for generations—methods that now begin to match the complexity of cancer cells themselves.”

“To overcome this obstacle, nanoparticles capable of delivering cargos specifically into a cell, present an opportunity as the next wave of modern cancer therapeutics.”

Classical cancer therapeutics generally involve various of chemotherapies, which in combination can create a potent method of fighting cancer. However, their efficacy is only matched by their potential to inflict collateral damage on healthy cells. In essence, one trades one dangerous ailment for a multitude of less-lethal problems. Chronic subjugation to certain chemotherapies has been linked to anemia, hypertension that contributes to heart disease, and infertility [4,5,6]. Chemotherapy also possesses the potential to initiate other effects, such as secondary cancers in the form of new neoplastic growths due to chemical treatment [7,8]. Nevertheless, perhaps the most concerning aspect of chemotherapy is cancer’s ability to develop resistance [9, 10]. This evolutionary paradigm manifests in the form of alterations in drug trafficking and drug efficacy. Anti-neoplasm drugs typically require internalization and functionality in order to be effective. Cancer cells exploit these requirements and develop resistance to drugs is two primary ways: i. decreasing the abundance of the drug through altered drug transport and enhanced efflux and ii. enzymatic deactivation of proteins required to activate the drug, rendering it impotent. Both mechanisms have been shown to be heavily rooted in genetics. MDR1, a gene encoding a promiscuous membrane transporter, is heavily upregulated in cancer cells, allowing increased efflux of therapeutic drugs [10, 11]. Similarly, downregulation of enzymes that convert non-toxic drugs into their effective counterparts confers resistance to the drug (e.g. DCK and Arabinoside) [10, 12]. As such, cancer manages to evade death while healthy cells are susceptible to the toxicity of chemotherapy. In light of this information, cancer therapeutics have encountered major a hurdle. To overcome this obstacle, nanoparticles capable of delivering cargos specifically into a cell, present an opportunity as the next wave of modern cancer therapeutics. Through the use of siRNA, RNA capable of gene-silencing via complementation with messenger RNA (mRNA), nanoparticles can perturb chemotherapy resistance mechanisms from a genetic standpoint. Combine this with classical chemicals capable of killing cancer cells, and the nanoparticles can disable the resistance mechanisms and deliver the final blow. It is a superweapon that beautifully takes the two simple tools already in place and optimizes them spatially and temporally.

While nanoparticles are elementary in principle, implementation of such a therapeutic is susceptible to both chemical and biological challenges. How will the release of drug be staggered to give the siRNA enough time to silence genes? Paula Hammond of MIT offers an ingenious solution. A clever “layer-by-layer” model of nanoparticles, composed of multiple layers intercalated with specific substrates, allows the chemotherapy drug to be enveloped by layers of siRNA [13]. This way, the internal architecture of the nanoparticle provides hierarchical control, allowing siRNA to disable resistance genes prior to a toxic chemical release. However, to minimize collateral damage of healthy cells, this potent superweapon must specifically target cancer cells. Here, specific ligands that bind to aggressive tumor cells can be intercalated into the shell of the nanoparticle, promoting interaction of nanoparticles specifically with cancer cells [14]. Finally, given the tendency for the immune system to destroy foreign objects, how will the nanoparticles hide from the defensive innate immune system? By coating the nanoparticle with negatively charged compounds, the half-life of the nanoparticle is increased, and the charged compounds add an element of stealth [15]. In recruiting a layer of water, the charged particles serve as an invisibility cloak for the nanoparticle, undetected by the immune system.

“In recruiting a layer of water, the charged particles serve as an invisibility cloak for the nanoparticle, undetected by the immune system.”

Already, this technology has been demonstrated to be a highly personalized and potent cancer therapeutic in mice [15]. Currently, it proceeds to clinical trial in efforts of developing a cancer therapeutic that is both safe and effective. However, nanoparticles are not limited to cancer therapeutics; integration with CRISPR-Cas9 gene-editing technology has also allowed target-specific genetic manipulations [16]. For being so miniscule, nanoparticles have the potential to change the future.
Nanoparticles, are the paradigm-shifting apples of the therapeutic world – with their high specificity for cancer cells and deadly combination of gene-silencing with poisonous toxins, they are a nightmare for cancer cells. However, just as apples acts as a symbol for health, nanoparticle serves as a beacon of light in the dark and tumultuous abnormality that is cancer.

REFERENCES

  1. Hanahan L and Weinberg R. 2011. Hallmarks of Cancer: The Next Generation. Cell. 144(5):646-74
  2. Ross S. et al. 2017. Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing. PLOS. 12(8): e0183390
  3. Fesnak A and Levine B. 2016. Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews. 16: 566–581
  4. Berger A. et al. 2010. Cancer-related fatigue”. Journal of the National Comprehensive Cancer Network. 8 (8): 904–31
  5. Pai V and Nahata M. 2000. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Safety. 22(4):263-302
  6. Ajala T. et al. 2010. Fertility Preservation for Cancer Patients: A Review. Obstet Gynecol Int. 10
  7. Errico A. 2014. Retinoblastoma—chemotherapy increases the risk of secondary cancer. Nature Reviews Clinical Oncology 11: 623
  8. Rüther U. et al. 2000. Secondary Neoplasias following Chemotherapy, Radiotherapy, and Immunosuppression. Contributions to Oncology (Beiträge zur Onkologie). 55
  9. Zuccala E. 2016. Chemotherapy: Clocking up resistance. Nature Reviews Cancer.
  10. Holohan C. et al. 2013. Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer. 13: 714-26
  11. Housman G. et al. 2014. Drug Resistance in Cancer: An Overview. Cancers. 6(3): 1769–1792.
  12. Flasshove M. et al. 1994. Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside. Leukemia. 8(5):780-5
  13. Deng Z. et al. 2013. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACSNano. 7 (11): 9571–84
  14. Dreaden E. et al. 2014. Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles. ACSNano. 8(8):8374-82
  15. Gu L. et al. 2017. A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-small Cell Lung Cancer. Clinical Cancer Research. Hammond
  16. Lee K. et al. 2017. Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nature Biomedical Engineering.

This piece was featured in Volume III Issue I of JUST.

2017-12-12T23:56:29+00:00 December 14th, 2017|