Use of a lipid nanoparticle system as a Trojan horse in delivery of gold nanoparticles to human breast cancer cells for improved outcomes in radiation therapy

Abstract

Background: Radiotherapy is commonly used for treating cancer. Novel sensitizers, such as gold nanoparticles (GNPs), are being used to enhance the local radiation dose. It is not known how the uptake and radiation dose enhancement of GNPs vary in synchronized vs unsynchronized (control) tumor cell populations. Successful application of GNPs in radiation therapy requires NPs to be accumulated within individual tumor cells at clinically feasible NP concentrations. Use of small GNPs as a radiation dose enhancer in the past required very high NP concentration, since the driving force for the uptake of smaller GNPs is low. We used a novel lipid-based NP of 50 nm diameter system as a Trojan horse to deliver smaller GNPs of size 5 nm (LNP-GNP) at 0.2 nM concentration. We investigated the changes in GNP uptake and survival fraction with the LNP delivery at different cell stages using human breast cancer as our tumor model and choosing the triple-negative MDA-MB-231 cell line. Results: Using the LNP-GNP system resulted in a 39-and 73-fold enhancement in uptake of 5 nm GNPs in unsynchronized and synchronized tumor cell populations, respectively. The NP uptake per cell increased from 800 to 1200 and from 30,841 to 88,477 for individual 5 nm GNPs and 5 nm GNPs incorporated in LNPs, respectively. After a radiation dose of 2 Gy with 6 MeV photons, synchronized tumor cell populations incorporated with LNP-GNPs produced a 27% enhancement in tumor cell death compared to the control (unsynchronized; no GNPs; 2 Gy). The findings of our experimental results were supported by modeling predictions based on Monte Carlo calculations. Conclusions: This study clearly shows that the cell cycle, GNPs, and radiation therapy can be combined to improve outcome of cancer therapy. Using the experimental data, we estimated the predicted improvement for a clinical treatment plan where 30 fractions of 2 Gy radiation dose were given over a period of time. Enhanced uptake and radiation sensitivity of a synchronous tumor cell population would produce a significant improvement in cell killing. For example, synchronizing cells and the addition of LNP-GNPs into tumor cells produced a 1000-fold enhancement in cell killing. Because the agents used for cell synchronization are in clinical practice, this approach may be a

Quantification of gold nanoparticle photon radiosensitization from direct and indirect effects using a complete human genome single cell model based on Geant4

“…For example, the endolysosomal pathway of GNPs can lead to the GNPs clusters of vesicles within cytoplasm in practice. 45 However, a more homogeneously distribution of GNPs in cells can simulate the average GNP distribution surrounding the nucleus to produce a universal estimate about dose enhancement due to the GNPs. This is an appropriate estimate and the reason why gold shell-like geometries have been adopted to approximate the distribution of GNPs as in the work of McKinnon et al 46 and Engels et al, 7 as well as our previous study.…”

Modulation of nanoparticle uptake, intracellular distribution, and retention with docetaxel to enhance radiotherapy

“…Both HeLa and MDA-MB-231 are widely used for drug research, previous work with our nanoparticle system has been performed with both cell lines. [82,86] Dosages as high as 60 µM have been investigated through some in vitro work, though with diminishing returns beyond 600 nM. [87,88] Hence, the dose range chosen for our assay was 0.5-500 nM (0.40-400 ng/mL) at 24 hours of exposure to identify the heel of the dose response curve (Figure 13a, b).…”

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

“…Ultrasmall gold nanoclusters have also emerged as a useful technology due to their near 100% renal clearance, allowing for the improved probing of disease when utilized as a biosensor [43]. Lipid-based nanoparticles are an avenue that is being explored due to their ability to encapsulate GNPs for radiosensitization purposes and simultaneously act as a drug delivery platform [44]. Utilizing liposomal nanoparticles as a 'smart' drug carrier can allow for controlled release of the internalized cargo, such as in response a NIR light source, allowing more control over the treatment process [45].…”