Blood-triggered generation of platinum nanoparticle functions as an anti-cancer agent

These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis.

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In the burgeoning field of nanotechnology, there has been an upsurgein the use of metals or metal compound nanoparticles (NPs) in living organisms. For instance, biosynthesis of CdTe quantum dots in earthworms generates metal NPs that are useful for live cell imaging1. Upon the discovery of magnetite particles in the human brain, iron oxide NP studies have revealed unique combinations of redox activity, surface charge and magnetic behavior2. The presence of iron oxide NPs in the brain insinuates that metal NPs can be safely applied in the human body. Indeed, several agents containing heavy metals are clinically administered. For example, platinum (Pt) is the main component in the anti-cancer drug cisplatin3, a mercury adjuvant is used in traditional Chinese medicine4 and gadolinium-containing contrast agents are used for radiology5. Since cisplatin is approved as a first line treatment for ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and leukemias, various cisplatin-based complexes have been generated for additional applications in cancer treatment6.

Based on the physicochemical properties of metals, the physiological milieu favors their transformation into metal NPs. We have previously demonstrated that ZnO NPs (bio-ZnO NPs) are spontaneously biosynthesized when animals are fed Zn ions in aqueous solution7. In addition, NPs generally become coated with a protein corona in the circulation. For example, Pt NPs become naturally coated with albumin to realize the same tumor-targeting properties as the FDA-approved paclitaxel-albumin complexes8. Interestingly, noble metal-based NPs (e.g., Pt, Au, Ag) can spontaneously absorb GSH, with the sulfhydryl group as a capping ligand9. This feature is important to cancer therapy since an increase in reduced glutathione (GSH) activity is the major mechanism of multidrug resistance in carcinomas10.

Here, we report the detection of biologically-formed Pt NPs in the circulation immediately after chemotherapy in humans. The size of these Pt NPs permits a long circulation half-life with a slow permeation through the glomerular filtration barrier. The dual tumor-targeting NPs accumulate in tumor regions, exert a prolonged effect via controlled drug release, exhibit good biocompatibility and reverse tumor cell drug resistance. Compared with other heavy metal elements (e.g., Ag, Cd) that are commonly used in the laboratory synthesis of NPs, Pt NPs that are autologously synthesized in a patient blood can be directly applied to cancer treatment without any modification.

References

1.    Sturzenbaum, S. R. et al. Biosynthesis of luminescent quantum dots in an earthworm. Nat. Nanotechnol.8, 57-60 (2013).

2.    Maher, B. A. et al. Magnetite pollution nanoparticles in the human brain. Proc. Natl. Acad. Sci. USA113, 10797-10801 (2016).

3.    Takahara, P. M., Rosenzweig, A. C., Frederick, C. A. & Lippard, S. J. Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature377, 649-652 (1995).

4.    Espinoza, E. O., Mann, M. J. & Bleasdell, B. Arsenic and mercury in traditional Chinese herbal balls. N. Engl. J. Med.333, 803-804 (1995).

5.    Zhou, Z. & Lu, Z. R. Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley. Interdiscip. Rev. Nanomed. Nanobiotechnol.5, 1-18 (2013).

6.    Harstrick, A. et al. Preclinical activity of a new platinum analogue, lobaplatin, in cisplatin-sensitive and -resistant human testicular, ovarian, and gastric carcinoma cell lines. Cancer Chemother. Pharmacol.33, 43-47 (1993).

7.    Wu, Y. Z. et al. Biosynthetic Mechanism of Luminescent ZnO Nanocrystals in the Mammalian Blood Circulation and Their Functionalization for Tumor Therapy. ACS Appl. Mater. Interfaces10, 105-113 (2018).

8.    Lin, T. et al. Blood-Brain-Barrier-Penetrating Albumin Nanoparticles for Biomimetic Drug Delivery via Albumin-Binding Protein Pathways for Antiglioma Therapy. ACS Nano10, 9999-10012 (2016).

9.    Sharma, S. Metal dependent catalytic hydrogenation of nitroarenes over water-soluble glutathione capped metal nanoparticles. J. Colloid Interface Sci.441, 25-29 (2015).

10.  Tew, K. D. Glutathione-Associated Enzymes In Anticancer Drug Resistance. Cancer Res.76, 7-9 (2016).

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Gen Zhang

Associate professor, Nanjing Medical University

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