The use of a nano-vehicle that mimics the rabies virus aids in the treatment of brain tumors.

Rabies as a Potential Treatment for Brain Tumors

Rabies is a lethal viral infection that affects the central nervous system. However, the deadly virus has been shown to be beneficial in the treatment of brain tumors (2017).

The Role of Nanoparticles in Targeted Drug Delivery

The special structure and biological properties of the nanoparticle delivery vehicle have inspired the mimicked designs of different nanoparticle delivery vehicles. The mimicked viral vectors have ‘longer systemic tolerance’ and greater therapeutic performance than traditional Nano vehicles, implying a more effective therapeutic medium for target delivery. Rabies virus (RABV) is a naturally occurring neurotropic virus of the Rhabdoviridae family that causes hydrophobia, swallowing problems, and panic attacks in host mammals. RABV has been encapsulated by a five protein envelope among which rabies virus glycoprotein (RVG) allows the virus bypass the blood-brain barrier (BBB) and enter the central nervous system (CNS) causing fatal encephalomyelitis (Lee et al. 2017).

Bypassing the Blood-Brain Barrier

It has been difficult to bypass the BBB and strategies have been made and proposed associated with the involvement of Nano vehicles relevant to the ‘RVG ligand’ of RAB (Thorpe et al. 2012). It has been found in studies about the involvement of RVG interacting specifically with the expressed ‘nicotinic acetylcholine receptor (AchR)’ on neuronal cells, enabling the entry of RABV to the central nervous systems, including the 29 residue short peptide (RVG-29) derived from RVG which is capable of binding to nicotinic AchR expressing neuronal cells (Neuro 2a (N2a) cells) and likely to be less interactive with non-neuronal cells. Therefore, the study says, the strategies involved in the use of RGV to the drug delivery system might appear helpful in the treatment of brain tumors (Lee et al. 2017).

Research Paper and Article Details

The research paper has been written by Changkyu Lee affiliated to School of pharmacy, Sungkyunkwan University, Republic of Korea and the article has been written by Josh Davis for ‘Health and Medicine.’ The research paper has been first published on January 30, 2017, and the article has been published on February 14, 2017, respectively. The paper has been written for the audience targeting researcher and medical personals along with the article written for all general and scientific backgrounds. The paper has been published in the ‘Journal of Advanced Materials’ and the article being published in the ‘Health and Medicine’ magazine.

Objective: Rabies Virus-Mimetic Nanorods for Drug Delivery

The paper has focused mainly on the mimicking of rabies virus as a Nano-vehicle to bypass blood brain barriers in the drug delivery system. Therefore the objective of the study has been focused on introducing a unique ‘rabies virus-mimetic silica coated gold Nanorods (RVG-PEG-AuNRs@SiO2)’ in the treatment of brain tumors using ‘gold Nanorods (AuNRs)’ with surface modified ‘RVG29’, to enable the blood brain barrier bypass and allow the central nervous system entry to the brain through nicotinic AchR.

Methods: Synthesis of Rabies Virus-Mimetic Nanorods

The study has majorly focused on the synthesis of AuNRs with shape similarities to RABV by utilizing a non-spherical nanoparticle gold plate (AuNP) by fabricating its chemical properties of crate variety of nanoparticle shapes. For creating rabies virus like AuNRs were first synthesized on longitudinally grown gold Nanorods by approaching a seeded growth synthesis method. Hydroquinone was used as a reducing agent over for increased efficiency, because of the ascorbic acid sensitivity of Nano growth particle.

In the next step, an induction of transverse growth on the AuNRs was done for the reduction of its AR to RVAB because of the possibility of partial or complete loss of LSPR due to transverse overgrowth of AuNRs. Therefore, a cysteine-induced method was used to block longitudinal growth and induce transverse growth on the AuNRs surface.

Next was to create the outer material layer on the AuNRs surface for synchronizing the expected ratio and mimic the outer glycoprotein layer of the rabies virus envelope. A ‘tetraethyl orthosilicate (TEOS)’ silica material was surface coated on the AuNR for completing the RABV structural mimicry. Furthermore, RVG peptide surface density on gold Nanorods was a crucial factor for cellular uptake. Therefore, RVG29 density has maximized the density of RVG29 on AuNRs@SiO2-NH2 surface mimicking the RABV glycoproteins. With a maintained significant LSPR, the designed RVG-PEG-AuNRs@SiO2 was able to mimic the size, shape, and surface function of rabies virus (Lee et al. 2017).

Major Findings of the Investigation

The study revealed that the rod shape and the nicotinic AchR interactions have increased along with the increase in the ‘localized surface plasmon resonance (LSPR) signal’ when exposed to ‘near-infrared (NIR)’ light in concordance to the ‘photothermal therapy (PTT).’

The study compared the in vivo and in-vitro characteristics like ‘cellular uptake and biodistribution of RVG-PEG AuNRs@ SiO2 and RVG-PEG-AuNPs@SiO2’ in the brain, spinal cord, and N2a cells of mice revealing that the ‘RVGPEG- AuNRs@SiO2’ have been much efficiently entering into N2a cells that express nicotinic AchR over ‘RVGPEG- AuNPs@SiO2, PEG-AuNPs@SiO2, and PEG-AuNRs@ SiO2 (without RVG29)’. The finding displayed that the mimicked gold Nanorods have been more frequently entering the cells than the plain spherical gold nanoparticle for over the limited duration of approximately 4 hours, pointing at the evidence that the presence of ‘RVG29 on AuNRs@SiO2’ which specifically binds to the nicotinic AchR on N2a cells has been a reason for its cellular uptake improvements.

The researchers believed that the mimicry of the size, shape, and surface of rabies has been directly possible through the in vivo brain targeting of superior ‘RVG-PEG-AuNRs@SiO2.’ However, the significant fractions of the same have been also located in the parts of kidney, lungs, spleen, and heart of the mouse (Lee et al. 2017).

Results Relating to Other Studies

For their unique photothermal and optical properties, Gold Nanorods have gained significant interest in biomedical applications (Zhang et al. 2012). In the best spectrum of imaging and therapy, NIR 70-950nm called ‘water-window’, gold Nanorods generate strong LSPR. The gold Nanorods have a noticeable advantage over the spherical rods at a broader light spectrum with an absorption coefficient 100-104 times higher than conventional dyes, providing them a very high photothermal efficiency. The temperature can be increased to 10-1000°C during NIR irradiation and the optimization resulting in the irreversible damage and tumor necrosis, regulating the hyperthermic treatment of cancers (Lee et al. 2017).

There have been few studies demonstrating the elevated tumor cells damage due to the temperature sensitivity of normal cells because of the hypoxic environment of tumors. The present study gold Nanorods have demonstrated a phenomenal LSPR in response to the NIR wavelength of 808 nm. According to the observations, the ‘rabies virus mimetic RVG-PEG-AuNRs@SiO2’ has clearly targeted brain tumor cells, facilitating its cytotoxic effects in N2a cells in contrast to other groups. The increased cytotoxicity has been caused due to the cellular rate uptake in the presence of RVG29 and high interactions with nicotinic AchR, ‘RVG-PEG-AuNRs@SiO2 internalized at a faster rate than PEG-AuNRs@SiO2.

The overall study results indicated ‘RVG-PEG-AuNRs@SiO2 have great potential for brain tumors on the basis of their superior targetability and NIR thermal response (Lee et al. 2017).

Future Investigation

The study has revealed great importance; however, leaving some unanswered questions regarding whether the gold particles only internalize the tumor cells or can enter the normal cells as well. If they can internalize the other cells of the body, it can result in adverse effects, therefore leaving a need for further investigation in this context.

Uniqueness of the Study

The study has been unique from others as it was focused on designing Nanorods instead of Nanospheres, providing a better light spectrum for absorption and thermal flexibility and has been based on bypassing the blood-brain barrier by mimicking the rabies virus structure, depicting the overall uniqueness.

References

Davis J. (2017). Copying rabies could provide a new to treat brain cancer. Retrieved from http://www.iflscience.com/health-and-medicine/copying-rabies-could-provide-a-new-way-... 4/17/2017.

Lee, C., Hwang, S.H., Lee, S., Kim, B., Kim, J. et al. (2017). Rabies Virus-Inspired Silica-Coated Gold Nanorods as a Photothermal Therapeutic Platform for Treating brain Tumors. Journal of Advanced materials, 29, 1-8.

Thorpe, B.L., Marchi, N., Guo, K., Ghosh, C., Janigro, D., Valerie, K., and Yang H. (2012).Nanomaterial-mediated CNS delivery of diagnostic and therapeutic agents. Adv Drug Deliv Rev, 15, 64(7), 605-13. doi: 10.1016/j.addr.2011.11.014.

Zhang, Z., Wang, M.L., Wang, J., Jiang, X.M., Li, H., Hu, Z., Ji, Y., Wu, X., and Chen C. (2012). Mesoporous silica-coated gold nanorods as a light-mediated multifunctional theranostic platform for cancer treatment. Adv. Mater, 24, 1418-23.