Liquid Metal Nanoparticles that locate and neutralize cancer cells

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(a) the formation of the liquid metal nanoparticles injected with the cancer drug (b) singular nano-droplet with ligands and cancer drug (c) nanoparticles entering the cancer cells (d) nanoparticles releasing the cancer drug inside the cell (e) chemical composition of the ligands in the nanoparticles (Yue et. al, 2015) [1].

Despite the diversity of nanoparticle applications in medicine, the introduction of inorganic material into the body has presented significant challenges. Many types of metallic nanoparticles can remain in the body for prolonged periods of time, and have the potential to bioaccumulate in cells, inhibiting metabolic processes that can eventually prove harmful for the body [1]. Nanoparticles made of liquid metal combined with emulsified ligands offer an effective design for a drug delivery system (DDS) that can release cancer fighting drugs into the body in a targeted and controlled manner.

Gallium-indium alloy (EGaIn) nanoparticles are a novel DDS not only because their nanoscale size provides a high surface area for ligand and drug attachment, but also due to their inherent property of bioconjugation, which allows them to easily form covalent bonds to biomolecules. To create the DDS, the liquid EGaln nanoparticles are mixed with the ligands thiolated (2-hydroxypropyl)-β-cyclodextrin (MUA-CD) and thiolated hyaluronic acid (m-HA), and are exposed to mild ultrasonic waves that facilitate the formation of nano globules. The ligands attach to the surface of these nanoparticles and prevent them from fusing together and oxidizing. The MUA-CD ligand has a receptor to attach to the Dox drug without reacting with it and the m-HA ligand is structured to fit into receptors that are abundant on the surface of cancer cells so it can latch onto them. The nanoparticles accumulate on the surface of the tumor until the cells engulf them. Inside the cell, the mildly acidic environment causes the nanoparticles to fuse together and release the surface ligands, also releasing the cancer drug. The EGaIn particles continue to fuse with each other and eventually degrade due to oxidation and produce Ga(III) [1]. The Ga(III) by-products are essential to creating an effective DDS, as they alter the membrane permeability of the nucleus in order to allow the Dox drug to intercalate into the DNA to stop tumor growth [2]. The drug-expelling molecular pumps in the nuclear membrane that the Ga(III) combats are the primary reason most chemotherapy drugs become ineffective [3]. The by-products of the EGaIn degradation are not only low toxicity but also have a high renal clearance rate, decreasing the likelihood of bioaccumulation in the tissues. In this way, engineered EGaIn nanoparticles can be used to actively identify and easily invade cancer cells with the use of natural biological mechanisms such as cell surface receptors and active and passive transport, in combination with low risk chemical reactions. This creates faster and more effective cancer treatment with minimal adverse side effects. 

References

  1. Lu, Yue, Quanyin Hu, Yiliang Lin, Dennis B. Pacardo, Chao Wang, Wujin Sun, Frances S. Ligler, Michael D. Dickey, and Zhen Gu. "Transformable Liquid-metal Nanomedicine." Nature Communications Nat Comms 6 (2015): 10066.
  2. Thorn Caroline F, Oshiro Connie, Marsh Sharon, Hernandez-Boussard Tina, McLeod Howard, Klein Teri E, Altman Russ B. "Doxorubicin pathways: pharmacodynamics and adverse effects" Pharmacogenetics and genomics (2010).
  3. Persidis, Aris. "Multidrug Resistance." Nature Biotechnology 17 (1999): 94-95. Web. doi:10.1038/5289
  4. Park J-D, Zheng W. Human Exposure and Health Effects of Inorganic and Elemental Mercury. Journal of Preventive Medicine and Public Health. 2012;45(6):344-352. doi:10.3961/jpmph.2012.45.6.344.

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Through receptor-mediated endocytosis this treatment has a fast, localized and direct effect. Not only do the EGaIn nanoparticles effectively transport the cancer drug into the cell, they also inhibit the drug resistance mechanism of tumors [2].

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The by-products of the nanoparticle degradation have been low risk and deemed as harmless substances. The only risk is the potential for gallium indium alloy poisoning which has not yet been detected [4].

 

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