Nanodiamonds: Synthesis, Properties, Toxicities and an update on its effective uses in Anticancer Drugs Deliveries

 

Adamu Safiyanu Maikifi¹, Damodharan N¹*

¹Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur - 603203, Tamil Nadu.

 

ABSTRACT:

Nanodiamonds (NDs) are allotropes of carbon nanoparticles that contain tetrahedral SP³ carbon atoms that have various superior properties of optical, chemical stability, and excellent physical properties and ability to form conjugate bonds with so many drugs for pharmaceutical and other medicinal applications. These NDs were synthesized through different techniques from simple detonation in a sealed container using friendly carbon materials to micronization of graphite in water, conversion of diamond micro powder into a glowing crystalline NDs and ultrasonic cavitation of graphite in an organic liquid medium. Exposure of NDs to the alveoli region, macrophages tissue showed low toxicity and when NDs injected after coated with serums to an insect species; Acheta domesticus showed limited toxicity to the insect species. Recent research findings demonstrated its uses in the conjugation and effective delivery of anticancer drugs such as doxorubicins, conjugates of curcumin, usnic acid, 5-fluorouracil and NDs. It was found to increase the solubility and efficacy of 10-hydroxycamptothecin, paclitaxel and also reduces the toxicity of cisplatin anticancer through conjugation. ND-doxorubicin conjugate provided more safety, reduction in myelo suppression, and used to withstand drug-resistant in liver and breast tumors and able to withstand expulsion by cancerous cells in mice. NDs enhance the delivery of nucleic acid in cancer treatment by 70 fold and increase the efficacy of lipofectamine. It was found NDs cause thick inhibition of cancerous cells associated with breast tumor and Hepatocellular carcinoma using curcumin, usnic acid, 5-Fluorouracil, and ND conjugate. It increase penetration of Hydroxyurea anticancer drugs and enhance solubility of paclitaxel when it used as nanocarriers and reduces toxicity of cisplatin in non-cancerous cells and at the same time more injurious to cancerous cells. Nanodiamonds cut the toxicity and increase the potency of anticancer drugs and therefore have a role to play now and in the future in anticancer drug formulations.

 

 

 

INTRODUCTION:

Nanotechnology recorded tremendous growth in the last couple of years with opportunities and uses in lot of fields, including medicine and engineering. Nanoparticles are thoroughly investigated in the drug formulation sector with the aim to produce better nanocarrirers for drug deliveries, which can overcome the current problems associated with conventional drug deliveries such as unpredictability, unspecific target deliveries and bio-incompatibility with other body tissues.

 

Nanoparticles have over the years being studied for improvement of existing products and treatment purposes. Nanodiamonds (NDs) are Nano size carbon materials which are octahedron in shape with a diameter of 2 to 8 nm. The NDs possessed various superior properties of optical, chemical stability, and extremely good Physical properties and high ability for surface uptake⁽¹⁾. It is bio-compatible and can form bonding with molecules such as genes and drugs for better delivery in the system. Recently many investigations prove their potentials as better carriers owing due to their excellent properties⁽²⁾. There are limitations associated with NDs as nanocarriers in the system because of the concern towards toxicities associated with carbon particles used as nanocarriers. Therefore, it was recommended for thorough studies of any possible toxicity before formulation. Another associated problem is short half-lives which makes them eliminated faster through opsonization by phagocytes and their use in sustained delivery are limited⁽³⁾. Hence, a simple technique is developed to modify it by conjugating ligands to the surface of the nanoparticles. Therefore with the above technique there is possibility for it use as effective nanocarrier especially for anticancer drug delivery even though special attention would be needed during the production⁽⁴⁾. According to a particular report ND particles have existed in earth and meteorites deposit for more than ten thousand years^(5,6). NDs were also found in petrochemical product in form of diamonoids. In overall the toxicity of NDs compared to other carbon nanoparticles is tolerable and hence it is bio-compatible with human tissues.

 

Fig. 1 Typical Chemical Structure of Nanodiamond

 

Chemotherapy is technique applied for treatment of tumor diseases using chemical agents; but because of the agents attack on both the tumor and normal cells, serious adverse effects were observed in the course of therapy. Now with more knowledge in the use and manipulation of NDs it makes it possible for drugs incorporation into NDs and then better delivered as it provides many advantages over free drugs such as controlled drug release, better bio-distribution and multidrug resistance, and such they are now hot topic for research^(7,8). NDs have also possessed qualities of collecting and retaining for long time within tumor cells and important for killing the cancerous cells.

 

Synthesis of nanodiamonds:

NDs could be produced through detonation or explosives of environmentally suitable carbon materials ^(9,10). In this process, the carbon materials bombarded using energy to produce NDs. The process takes place in a closed container of gas or H₂O _(l). At the end of the process ND particles were obtained (with 4-5 nm in diameter) together with other metals⁽¹¹⁾. Amans⁽¹²⁾ produced NDs using vapor deposition technique by converting graphite into Nano size diamond. The manufactured NDs are of 5-15nm in diameter and a central core covered with 3-4 nm thick graphitic-like material and other metals (silver, lead, copper)⁽¹³⁾. Therefore the NDs should be purified before usage. Boudou⁽¹⁴⁾ developed a new method of manufacturing high-yield fluorescent NDs. They performed that by converting micro-powder of diamond material into mixture of tiny crystalline glowing fluorescent NDS through milling at exalted temperature and pressure for a 24 h. The process gives ND with an average particle size less than 10 nm and just fractional product output. Production of effective and cheap NDs is very important. Khachatryan⁽¹⁵⁾ were able to produce a micro diamond of average size of 6-9 um through use of low-frequency sound wave against graphite in an organic liquid by heating in atmospheric pressure at 120°C with 10% output. Regardless of the technique or manufacturing ways NDs comes always with impurities and a proper purification needed before use.

 

Properties of nanodiamonds:

Structural Property:

The superior properties of NDs possessed results from hard diamond itself and then the nanosize of the particles. Diamonds from time immemorial they are the hardest body and it has an optical prowess. ND consists of tetrahedral sp3 carbon atom crystals which contain a lot of attached functional groups⁽¹⁶⁾. Structurally ND contains outer shells attached with a several functional group and an inner shell⁽¹⁷⁾. There are two models that explain the outer shells through X-ray analysis; the first model is explain shapeless shell with prominent and rich in sp2 carbon and a second model of sp2 resembling a layer of graphene forming a structure known as “Bucky-diamond”⁽¹⁸⁾. NDs particles are able to form bonds with different groups of particles and act freely and with freedom of flexibility due to the several functional groups and the type of angular bond, it can handle which allows it swindle in plain or stretch in a twist⁽¹⁹⁾. The outer shell has majorly functional group; pyrones, phenols, sulfonic, hydroxyl groups, carboxylic acid, anhydride, and epoxide groups. Carboxylic groups, made it possible for NDs suspensions soluble in H₂O _(l), and ability to mixed thoroughly with water-soluble agents such as 4-hydroxy tamoxifen and purvalanol ⁽²⁰⁾.

 

Fig. 2: Structure of ND Particle with surface functional groups

 

Fluorescence Property:

ND possessed nitrogen–vacancy (NV) group and this gives it good fluorescence. The valence group could be produced by bombarding ND at high temperature of about 800^oC in a vacuum and allow to cool^(21,22). Two forms of NV group centers are formed which are neutral (NV0) and negative (NV-) charged centers. Negative NV– group is the most important because of resonance (electron paramagnetic) and ability to fluorescence and important for quantum manipulation⁽²³⁾. The synthesis fluorescence NDs occur in high pressure and temperature and then they are grinned to nanosized particle (less than 10 nm) NDs⁽²⁴⁾. A recurring luminescence is seen from NV centers during detonation of NDs synthesized from a trinitrotoluene and hexogen precursor⁽²⁵⁾. Continuous rays have also recently been detected from NV centers trapped in larger (>20 nm) NDs produced from trinitrotoluene and hexogen⁽²⁶⁾. Size-related proximity of surface defects and many internal defects might be the reason for the low fluorescence intensity of ND produced from explosives. This is supported by the demonstration of a very high content (up to 1%) of NV defects in detonation ND after sintering at temperature 800 °C and pressure 6 GPa which increases the ND sizes. Fluorescent particles can also be produced by linking^(27,28) or adsorbing⁽²⁹⁾ various fluorophores on ND. Fluorophore conjugated NDs can travel through cellular compartments of varying pH without deterioration of the surface-conjugated fluorophore or destruction of cell viability over long periods of time⁽³⁰⁾. Bright blue colored fluorescent ND has recently been produced by covalent linking of carboxylic groups with octadecylamine group on ND surface⁽³¹⁾. Fluorescent NDs possessed good qualities of large surface area and it is bio-compatible with capacity for effective drug delivery and medical imaging applications^{(32, 33)}.

 

Nanodiamond toxicities:

It is a known fact that crystalline carbon diamonds are harmless, though it will be awkward and dangerous to assume the same for Nano diamonds due to the fact that so many methods of production and purification were used by different producers and researches to decide otherwise is critical and of utmost concern⁽³⁴⁾. Research was conducted to find out the behavior and pattern of cell viability, gene activity, and physiological behavior when NDs were exposed to the system⁽³⁵⁾. NDs injected within the trachea region reported low pulmonary toxicity, with the amount of ND in the alveolar region decreasing with time, and macrophages burdened with NDs seen in the bronchia for 28 days after exposure and intravenously administered ND mixture at high doses did not alter serum indicators of liver and systemic toxicity ⁽³⁶⁾. Experiments conducted through the worm model by injecting glowing NDs to a gene which controls the immune response and stress level of cells (DAF-16) and green fluorescent protein (GFP) revealed that glowing ND does not induce stress and is not harmful which show it use in medical imaging. Julia⁽³⁷⁾ performed an experiment using Model of insect species; Acheta domesticus. The insect was exposed to NDs for long time through its diets and the result indicated an alteration in reproduction pattern of the insect (Orthoptera) and the EPR analysis revealed changes in the life span of the insect off springs. Jing⁽³⁸⁾ investigated the interaction of NDs with Hela cells using free NDs and serum coated NDs. The images of Transmission electron microscope of Hela cells mixed with NDs in and also another mixed with both NDs and serum are shown in Fig 3. The Hela cells mixed with NDs and coated with serum showed no toxicity to the Hela cells (Fig. 3 A and C). But in the dispersion without serum the NDs injured the Hela cells (Fig. 3 B and D).

 

Fig. 3 Images of Hela cells before and after incubation with NDs and with both NDs and serum

 

Recent findings on NDs use in anticancer drug delivery:

Efficient drug delivery of anticancer is possible due to the excellent properties NDs possessed; safety and the large surface area to adsorbed different therapeutics substances coupled with high solubility etc. An experimental study has demonstrated the efficacy and safety of ND conjugated delivery of anticancer drugs; doxorubicin in mice. ND–doxorubicin conjugates used to treat drug-resistant liver and breast cancerous cells in mice. The ND greatly reduced the tumors to expel the doxorubicin and the circulation half-time of the ND–Dox cojugates was found to be 10 times that of free doxorubicin⁽³⁹⁾. And also it does not cause myelosuppression (which is high when free Doxorubicins are used) and there is significant reduction of tumours growth with no mortality (Where as lanky dose of Unconjugated Dox produced LD50 effect) in mice. NDs coated with polyethylenimine 800 (PEI800) for delivery of nucleic acids have shown a 70-fold enhancement of GFP plasmid transfection efficacy while maintaining the less toxic properties of PEI800⁽⁴⁰⁾. And ND–PEI800 delivery of siRNA to silence GFP expression resulted in increased efficacy over lipofectamine (a widely used delivery platform) in physiological conditions⁽⁴¹⁾. A range of other cargos delivered including covalently attached drugs^(42,43), proteins^(44,45), small molecules under acidic conditions (which are commonly observed in tumours)⁽⁴⁶⁾ and siRNA for specific cancers⁽⁴⁷⁾. Garg⁽⁴⁸⁾ developed a new strategy to deliver an anticancer drug through conjugation with ND. They were able to prepare the ND-conjugated anticancer drug; NDs with curcumin, Usnic acid and 5-Fluorouracil. The experiment demonstrated an effective delivery of the conjugate and it also showed a thick inhibition against Hep-G2 and MCF-7 cancer cells⁽⁴⁹⁾. Paclitaxel (PTX) is effective drug used in the treatment of breast, ovarian, and so many other cancers but it is a limitation from its use through oral delivery because it’s poor solubility. To enhance its usage the drug mixed with NDs after it was been hydrolyzed and thus solubility of the drug improved and the percentage in vitro drug release was found; 97.32% for the period of 70 h⁽⁵⁰⁾. In another research⁽⁵¹⁾ was able to promote the efficacy and better cancerous cells recognition of PTX through conjugation with a functional fluorescent ND and addition of EGFR monoclonal antibodies. Also in a different research it was found conjugation of an anticancer drug 10-hydroxycamptothecin and nanodiamonds increases it penetration and solubility. The conjugation was carried out by addition of NDs and step wise addition of NaOH to enhance drug loading. Toxicity of Cisplatin to healthy cells restrict and makes it use unsuitable in treatment of cervical cancer⁽⁵²⁾ but with advancement in nanotechnology when adsorbed into an oxidized ND it gave an in vivo pH control release. The release in the blood is minute while in the cytoplasm of the cancerous cells the release became high and thus cut it toxicity in the blood streams⁽⁵³⁾. Conjugation of both Cetuximab and Cisplatin combination together with NDs was demonstrated and in the experiment NDs mixed with Cetuximab followed by addition of Cisplatin to form cetuximab-NDs-cisplatin (CNC) conjugate. The conjugate efficacy was found 40% more against hepatocellular carcinoma (HepG2) in human as when compared with using the un conjugated drug and the cetuximab-NDs-Cisplatin mixture promote selective cytotoxicity and the delivery is in controlled way⁽⁵⁴⁾. Due to hydrophilic nature of Gemcitabine which is anticancer in management of prostate its use is no longer suitable and free Gemcitabine accumulates both in healthy cells and cancer cells without specific recognition. To offer solution to this limitation a pegylated ND was adsorbed using reversible addition-fragmentation chain-transfer polymerization and the results showed decrease in toxicity and as such the ND-PEG provide a better delivery^(55,56).

 

Table 1 Anticancer drug conjugates with NDs and their applications

Anticancer agent	Nanoparticle	Conjugation	Application
Doxorubucin(Dox)	Nanodiamond (ND)	ND-Dox	·     Increase potency by 10 fold ·     Decrease in myelosupression effect
5-Fluorouracil(5-Flu)	Nanodiamond (ND)	ND-Curcumin-usnic acid-5-Flu	·     Extreme inhibition against Hep-G2 and MCF-7 cancer cells
Paclitaxel (Pc)	Nanodiamond (ND)	ND-Pc	·     Enhance solubility
10-hydroxycamptothecin(10-Hcp)	Nanodiamond (ND)	ND-10-Hcp	·     Increase in solubility and hence improve penetration
Cisplatin(C)	Nanodiamond (ND)	ND-C	·     Promote specific cancer cell recognition and damage
Cetuximab + Cisplatin (Ce-C)	Nanodiamond (ND)	ND-Ce-C	·     Increase in efficacy against Hepatocellular carcinoma (Hep-G2)
Gemcitabine(G)	Nanodiamond (ND)	ND-G-PEG	·     Improve Penetration rate ·     Reduction in cytotoxicity

 

CONCLUSION:

ND possessed a lot of qualities that attracted a lot of researches; from its synthesis using various ways, purification and identification to its application on various fields (pharmaceutical, Medicine, Engineering, etc.). This article concentrated on a review of many ways for its synthesis, the possible toxicities both on human cells and other organisms, the superior characters it possessed which makes it possible for various conjugation and effective anticancer drug deliveries. So the excellent qualities it possessed makes it possible to form conjugates with various anticancer drugs for effective drug delivery with a more superior target cancerous recognition, limited toxicity to normal cells and multiple fold efficacies as compared to using free unbounded anticancer drugs. Recent update in researches provides marvelous future uses in anticancer drug delivery formulations.

 

CONFLICT OF INTEREST:

There is no conflict of interest.

 

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Received on 21.12.2019           Modified on 05.02.2020

Accepted on 19.03.2020         © RJPT All right reserved