Enhancing Cancer Radiation Therapy with Cell Penetrating Peptide Modified Gold Nanoparticles

Research Article

Austin J Biomed Eng. 2016; 3(1): 1033.

Enhancing Cancer Radiation Therapy with Cell Penetrating Peptide Modified Gold Nanoparticles

Send Kah Ng¹, Liyuan Ma¹, Yuting Qiu¹, Xiaojie Xun², Thomas J. Webster1,2,3 and Ming Su1,2*

¹Department of Chemical Engineering, Northeastern University, Boston, Massachusetts, USA

²Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Sciences, Wenzhou, Zhejiang, China

3Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia

*Corresponding author: Ming Su, Department of Chemical Engineering, Northeastern University, USA

Received: April 20, 2016; Accepted: June 22, 2016; Published: June 24, 2016


Radiotherapy is one of the most prevalent methods for cancer treatment. However, a challenge for cancer radiotherapy is that therapeutic doses used can damage neighboring normal cells. This paper describes a new method to enhance radiation therapy by delivering gold nanoparticles into cancer cells, where gold nanoparticles were modified with virus-derived cell penetrating peptides (CPPs) and Poly (Ethylene Glycol) (PEG). PEG was used to improve nanoparticles blood circulation time, and CPPs were used to enhance internalization of the nanoparticles into cells. The internalization of CPP-PEG modified gold nanoparticles in cancer cells (HeLa cells) was confirmed with differential interference contrast imaging. A variety of assays (such as bright field imaging, MTT, DNA damage, reactive oxygen species and immunofluorescence) were used to detect cellular and genetic damage in cancer cells. We found that CPP-PEG modified gold nanoparticles caused more cellular and DNA damage than gold nanoparticles at the same radiation doses due to enhanced generation of free radicals. In contrast, damage was not severe for normal fibroblasts cells under the same conditions. This method can potentially be used to severely damage DNA and other cellular structures of cancer cells, while minimizing damage to normal cells during radiation therapy.

Keywords: cell penetrating peptides; gold nanoparticles; radiation therapy


Currently, chemotherapy, surgery and radiotherapy are the most effective methods to treat cancer [1]. Radiotherapy targets and destroys tumor with ionizing radiation. The laser generates free radicals that damage various cellular components including DNA. One of the advantages of using radiotherapy is that it can kill tumor even though they are intermix with normal healthy tissue [2]. Hence, more than 50% of cancer patients received radiotherapy treatment. However, the therapeutic doses used during radiotherapy can damage nearby normal cells [3-5]. Various chemicals and nanoparticles were tested to act as radiosensitlzers to enhance radiotherapy [6].

Despite its essential role in maintaining cell function, cell membranes present a major barrier for intra-cellular delivery of therapeutic nanoparticles [7]. Hence, even though ions or nanoparticles of high atomic number elements (such as gold, platinum and bismuth) have been used to enhance radiation therapy by absorbing ionizing radiation and generating free radicals at high yield [8-10], the measured enhancement effect due to nanoparticles has been negligible, likely because inefficient nanoparticles were present in cancer cells and X-ray generated free radicals cannot reach the vicinity of DNA to cause damage [11,12].

Nanoparticles can be modified to have desirable surface properties to allow for uptake and targeted delivery into cells and subcellular locations [13,14]. Non-viral vectors such as amino-modified silica nanoparticles, iron oxide nanoparticles, carbon nanotubes and gold nanoparticles have been used to deliver nucleic acids in transfection assays [15-18]. In particular, gold (Au) nanoparticles are stable, non-toxic and easy for surface modification, making them a suitable candidate to deliver molecules into cells [19-23]. However, to reach their full potential in cellular applications such as radiotherapy, robust methods must be developed to allow for the controlled uptake of gold nanoparticles into cells. This requires the gold nanoparticles to be functionalized with engineered coatings to promote their cellular uptake and targeted delivery.

Poly ethylene glycol (PEG) was used to coat nanoparticles to improve their blood circulation [24]. However, PEG interactions with cell surface ligands prevent nanoparticles intra-cellular uptake. One solution to use cell penetrating peptides (CPPs). CPPs are relatively short cationic and/or amphipathic peptides and are efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo [25]. The various molecular cargo delivered by CPPs ranges from nanosize particles to small chemical molecules and large fragments of DNA. The “cargo” is associated with the peptides either through chemical linkage via covalent bonds or through non-covalent interactions [26]. The function of the CPPs is to deliver the cargo into cells, a process that commonly occurs through endocytosis with the cargo delivered to the endosomes of living mammalian cells [27,28].

In our study, coating of gold nanoparticles with PEG prevents the gold nanoparticles from aggregation and allows the nanoparticles to evade immunological response in vivo [29]. This gives the nanoparticles a longer circulation time in the body and increases their chance to accumulate inside the cancer cells. The CPPs with multiple arginine residues and positively charged motif derived from human immunodeficiency virus (HIV) Transcriptional Activator Protein (Tat), has been shown to mediate the endocytic uptake of a number of different nanoparticles in eukaryotic cells [30].

This paper describes a new method to enhance X-ray radiation killing of cancer cells by internalizing CPP-PEG modified gold nanoparticles (as radiosensitizers) into cells (Figure 1A). We hypothesized that at a given irradiation dosage, if gold nanoparticles could be placed specifically inside cancer cells and close to cell nuclei, more free radicals would be available to cause DNA damage. Hence, the total radiation dose could be reduced to receive the same treatment effect on cancer cells without severely damaging the healthy cells nearby.