pH-sensitive nanoparticles reduce cancer growth by deoxygenating tumor tissue [PreClinical]
1. Under mildly acidic in vitro conditions, silicon-based nanoparticles (NPs) effectively scavenged dissolved and hemoglobin-bound oxygen (O2) and reduced breast cancer cell viability. Â
2. In a mouse model of breast cancer, treatment with NPs reduced tumor tissue oxygenation and diminished tumor progression without detectable damage to vital organs.
Evidence Rating Level: 2 (Good) Â Â Â Â Â Â
Study Rundown: Though starving tumors of O2 and nutrients has been regarded as an approach to impede rapid growth, feasible techniques to induce starvation remain elusive. In this work, oxygen-scavenging NPs were developed to deoxygenate tissues under acidic conditions and consequently block the proliferative capacity of tumors.
In vitro, mildly acidic environments activated the magnesium silicide (Mg2Si) NPs to produce reactive silane groups that acted as O2 scavenging molecules. In solutions with pH<6.5, NPs significantly reduced dissolved O2 levels to undetectable concentrations within several hours and maintained this effect for as long as 1 week. Additionally, the ability for NPs to deoxygenate solutions of oxyhemaglobin (oxyHb) was examined since most O2 is delivered in a hemoglobin-bound state. Treatment with NPs at pH 6.5 caused a significant loss of oxyHb and gain of deoxyhemaglobin (deoxyHb) whereas NPs in pH 7.4 incited no changes. In breast cancer cells exposed to NPs under acidic conditions, significant reduction in proliferation rate was accompanied with increased cell apoptosis. When tested in a mouse model of breast cancer, NP treatment significantly reduced O2 saturation levels and gross tumor growth over the course of 16 days. Importantly, NPs had undetectable negative effects on the tissue health of main organs such as the liver and lung.
This work provided promising preliminary evidence suggesting that tumor O2 starvation can be achieved through a nanotherapeutics approach. Long-term efficacy and safety must be evaluated to push this therapy into clinical use, especially since the oxygen-scavenging process generates microparticle by-products that can cause off-target organ damage.
Click to read the study in Nature NanotechnologyÂ
Relevant Reading: A review of stimuli-responsive nanocarriers for drug and gene delivery
In-Depth [animal study]: Mg2Si NPs were chemically synthesized and tested for their deoxygenating capabilities in buffered solutions with pH 7.4, 6.5, and 4.5. Dissolved O2 concentrations of the solutions were measured using an O2 microelectrode every several hours and up to 7 days after NP addition. While the O2 concentration remained unchanged at pH 7.4, O2 levels of the acidic solutions became undetectable within 8 hours and remained steady for 1 week. Deoxygenation of oxyHb by NPs was examined through the addition of fresh blood collected from female BALB/c mice into solutions with pH 7.4 and 6.5. Solution samples were analyzed using UV-vis spectroscopy, which indicated a loss in absorption peaks at 542nm and 577nm (oxyHb) and a gain of a band at 555nm (deoxyHb) in the mildly acidic condition.
Proliferation studies performed on MCF-7 breast cancer cells demonstrated that 2mM NP treatment led to a nearly 50% reduction in growth relative to the control (p<0.001). At higher NP doses (5mM and 10mM), negative proliferation rates were observed, suggesting cell death. Flow cytometry confirmed that high-dose NP treatment led to nearly 3-fold and 5-fold increases in apoptotic cells, respectively.
In the mouse experiment, BALB/c mice were bilaterally injected with 4T1 breast cancer cells 10 days before treatment. Intratumoral injection of NPs (1M) triggered a significant drop in tumor blood O2 saturation over several hours whereas the saline control produced no effect. In the 16 days after treatment, tumors given saline injections rapidly grew in volume whereas tumors with NP injections remained unchanged (p<0.001, n=5 per group). At the end of treatment, histological H&E staining of vital organs (heart, spleen, lung, liver, and kidney) demonstrated negligible changes to tissue structure.
Image: PD
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