This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to further improve chemotherapy through controlled delivery of chemotherapeutics, while local radiotherapy dose can be enhanced by targeting the GNPs to the tumor. There have been over 20 nanotechnology-based therapeutic products approved for clinical use in the past two decades. Hence, the goal of this review is to understand what we have achieved so far and what else we can do to accelerate clinical use of GNP-based therapeutic platforms to minimize normal tissue toxicity while increasing the efficacy of the treatment. Nanomedicine will revolutionize future cancer treatment options and our ultimate goal should be to develop treatments that have minimum side effects, for improving the quality of life of all cancer patients.

One of the major issues in cancer radiotherapy (RT) is normal tissue toxicity. Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to enhance the local RT dose has been tested successfully. However, it is not known how GNPs interact with other stromal cells such as normal fibroblasts (FBs) and cancer associated fibroblasts (CAFs) within the tumour microenvironment. It is known that FBs turn into CAFs to promote tumour growth. Hence, we used FBs and CAFs along with HeLa (our cancer cell line) to evaluate the differences in GNP uptake and resulting radiation induced damage to elucidate the GNP-mediated therapeutic effect in RT. The CAFs had the largest uptake of the GNPs per cell, with on average 265% relative to HeLa while FBs had only 7.55% the uptake of HeLa and 2.87% the uptake of CAFs. This translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and HeLa (9.8%) compared to FBs (8.8%) with RT treatment. This difference in DNA damage due to selective targeting of cancer associated cells over normal cells may allow GNPs to be an effective tool in future cancer RT to battle normal tissue toxicity while improving local RT dose to the tumour.

The combined use of radiation therapy and chemotherapy is commonly being used in cancer treatment. The side effects of the treatment can be further minimized through targeted delivery of anticancer drugs and local enhancement of the radiation dose. Gold nanoparticles (GNPs) can play a significant role in this regard since GNPs can be used as radiation dose enhancers and anticancer drug carriers. Anticancer drug, bleomycin, was chosen as the model drug, since it could be easily conjugated onto GNPs through the gold–thiol bond. Gold nanoparticles of size 10 nm were synthesized using the citrate reduction method. The surface of The GNPs was modified with a peptide sequence (CKKKKKKGGRGDMFG) containing the RGD domain and anticancer drug, bleomycin. Human breast cancer cells (MDA-MB-231) were incubated with 0.3 nM concentration of GNP–drug complex for 16 h prior to irradiation with a 2 Gy single fraction of 6 MV X-rays. After the treatment, cells were trypsinized and seeded in 60 mm dishes for clonogenic assay. Damage to DNA was probed using immunofluorescence assay. Cancer cells internalized with the GNP–drug complex had a 32 ± 9% decrease in cell survival and statistically significant enhancement in DNA (deoxyribonucleic acid) damage as compared to control cells (irradiated with no GNPs) after receiving a radiation dose of 2 Gy with 6 MV photons. The experimental results demonstrate that GNP-mediated chemoradiation has the potential to improve cancer care in the near future through enhancement of the local radiation dose and controlled delivery of anticancer drugs.

Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.

Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25- and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of “smart” nanomedicines that would constitute the next generation of cancer therapeutics.