Abstract
BackgroundRadiotherapy 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.ResultsUsing 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.ConclusionsThis 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 simple and cost-effective way to further enhance local radiation dose. Finally, this study provides a novel lipid-based NP platform to further improve GNP-mediated radiation therapy through synchronization of breast cancer cell population.
Highlights
According to the World Health Organization, cancer is the second leading cause of death globally and was responsible for an estimated 9.6 million deaths in 2018
We will refer to the lipid nanoparticles (LNP)–gold nanoparticles (GNPs) as “50 nm LNP–GNPs” and to smaller GNPs as “5 nm GNPs”
A Transmission electron microscopy (TEM) image of 5 nm GNPs used for encapsulation in LNPs is given in Additional file 1: Fig. S1A
Summary
According to the World Health Organization, cancer is the second leading cause of death globally and was responsible for an estimated 9.6 million deaths in 2018. Radiation therapy presents the challenge of delivering a dose to tumor cells, while sparing surrounding normal tissue, through which ionizing radiation must inevitably pass. To help overcome this limitation, the introduction of high atomic number (Z) materials, such as gold nanoparticles (GNPs) as radiation dose enhancers into current radiation therapy protocol is being studied to improve the local therapeutic effects (Cho and Krishnan 2013; Chithrani et al 2010; Hainfeld et al 2004; Butterworth et al 2013). Radiotherapy is commonly used for treating cancer Novel sensitizers, such as gold nanoparticles (GNPs), are being used to enhance the local radiation dose. 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
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