INTRODUCTION:

Nanodiamonds are nano-sized carbon based particles coming under the family of nanocarbons. Since nanodiamonds have ability to emit bright fluorescence, they were used primarily as biological imaging agents after the introduction of nitrogen defects. Recent researches show that they have potential effects as biosensors and drug delivery carriers in cancer treatment and used in dental implants.

Nanodiamonds based drug delivery system is a new and innovative technology in medical and pharmaceutical sciences.

As compared to other nanoparticles, they have size selectivity, purity, aggregation retention, surface functionality and colloidal stability ^[1]. Nanodiamonds are now widely used because of their inexpensive large-scale synthesis, small particle size, and high biocompatibility ^[2]. Its large surface area, high absorption capacity and chemical inertness were made advantageous to use as potential medical agents.

Nanodiamonds are now widely used in cancer treatment because they provide retention of drug in tumour cells due to the attachment of drug to the nanodiamonds helps them to remain in tumour cells longer than the drug its own. Nanodiamond–insulin cluster is integrated in ointments, gels, bandages or suture materials for healing wound ^[3].

Structure of nanodiamonds

Nanodiamonds are carbon allotropes of approximately 2 to 8 nm in diameter. Surface of each nanodiamond possess functional groups for wide spectrum of compounds. These are ultra-disperse diamonds having crystalline consists of two close packed inter penetrating face centered cubic lattice; one is shifted with respect to the other ^[4]. They are clustered carbon atom with both graphite (sp²) and diamond (sp³) bonds. These two bonds are interchangeable for eg; the stretched face of diamond is a grapheme plane. In reverse, the puckered grapheme may become a diamond surface.^[5]

Carbon has 6 electrons with four valence electrons. sp² hybridizated carbon atoms leads to the formation of the two dimensional planar hexagonal structure of graphite. sp³ hybridization forms a rigid diamond structure with tetrahedral symmetry, where valence electrons form a σ bond with the neighbouring carbon atoms. The lack of free electrons in their bulk structure characterised for their inertness ^[6].

Significance of nanodiamonds:

a. Prolonged duration of drug release.

b. High drug loading capacity

c. Provide localised action and minimize the side effects.

d. Nanodiamonds can combine with a large variety of drugs and RNA.

e. Immunologically inert.

f. Advantageous property in tumour targeting.

Properties of nanodiamonds:

· Hardness:

Diamonds are 50 times harder than Titanium and Stainless steel and have better physical and chemical properties than Titanium and SS. Their toughness was important because it makes them suitable for implant and surgical in biomedical fields^[7].

· Chemical inertness:

Suitably coated (with alloy of Ti6Al4V) Nanodiamonds are highly resistant to corrosive biological environment ^[8].

· Surface area:

Nanodiamonds have a large surface area, it helps to place large amount of drugs on the particles ^[9].

· Solubility:

They are readly soluble in water, thus high bioavailability and easily travel throughout the body ^[9].

· Optical properties:

They have excellent optical properties, thus it can be successfully applied as biomarkers or a bio label ^[10].

· Chemical modification:

Chemical modification by carboxylation made the nanodiamonds with good physical adsorption properties mediated by hydrophobic and hydrophilic interaction lead to immobilization of biomolecule ^[11]for applying anodiamonds as potential biosensor.

· Aggregation:

Nanodiamonds tend to aggregate and a typical suspension of nanodiamonds contains larger aggregates and these aggregates are useful in chromatography or drug delivery. The aggregates are deaggregated in to individual particles in many application often needed beneficially from the advantage of nanodiamonds ^[12].

· Flurescence:

This is due to the presence of nitrogen-vacancy centres (a nitrogen atom next to a vacancy) in nanodiamonds. Nanodiamonds can be created by irradiating the nanodiamonds with high energy particles (electrons, protons and helium ions) followed vacuum annealing at 600-800°C ^[13].

Biocompatibility of nanodiamonds:

Biocompatibility of nanodiamond should be thoroughly studied while applying to biological systems. The studies reveal that nanodiamond with small size of 2-10 nm are not toxic to cells. Although, it should be seriously consider the unique interactions with biological systems in prior to its biological application ^[14]especially the respiratory toxicity since it will spread to the air during the manufacturing and processing ^[15].

In a study on mice, subcutaneous exposure to nanodiamonds for three months showed no inflammatory symptoms shows good biocompatibility with organisms^[16]. Since the nanodiamondshave very small size the radionucleotide tracer technique was used to detect its distribution and it was observed that the nanodiamonds were mainly distributed in lung, spleen and liver. Engulfment by lung macrophages might be the most important way to remove nanodiamonds ^[15].

Types of nanodiamonds:

There are mainly three types of nanodiamonds

1. Commercial nanocrystalline diamonds particles.

2. Commercial ultrananocrystalline diamond particles.

3. Diamondoids.

Commercial nanocrystalline diamond particles:

Nanocrystalline diamond particles with characteristic sizes can be of two type, monocrystalline particles and polycrystalline particles^[17]. Monocrystalline nanoparticles are obtained by processing micronsized monocrystalline diamond particles, which are in turn, a by-product of natural diamond. Monocrystalline particles are of two types, natural and synthetic HPHT. The natural monocrystalline diamond powders are the purest form in the class of nanodiamonds materials.

Commercial ultrananocrystalline diamond particles:

This type of nanodiamond is most frequently used for therapeutic application such as drug delivery platforms for nanoscale medicine, protein absorption, carrier for genetic material in gene gun ballistic delivery and as enter sorbents.

Diamondoids:

They were highly rigid, well defined, readily derivatizable structure, and so called “higher diamondoids”. Higher diamondoids were extracted from petroleum as diamond molecules in the form of nanometer sized rods, helices, discs, pyramids, etc ^{[18, 19]}. However the mechanism of formation in petroleum still remains unknown ^[1].

Methods for synthesis of nanodiamonds:

Nanodiamonds can be synthesised by three methods. They are,

· Detonation nanodiamond.

· Ultrasonic cavitation method.

· Pulsed-laser irradiation.

Detonation nanodiamond:

Detonation nanodiamond is diamond that originates from detonation. It is also called ultra-dispersed diamond. A nanodiamond can be formed from a mixture of trinitrotoluene and hexogen (figure 1) by detonation. The yield of diamond will depend upon the synthesis condition, especially on the cooling medium heat capacity in the detonation chamber (water, air, co₂, etc.). High-resolution TEM and X-ray diffraction revealed that the size of the diamond grains was around 5 nm. Due to aggregation and spontaneous formation of micrometre sized cluster the grains were very unstable ^[20].

TNT Hexogen

Figure 1: TNT and Hexogen

Ultrasonic cavitation method:

In this method the nanodiamonds are prepared from a suspension of graphite in organic liquid at atmospheric pressure and temperature. Phenomenon of cavitation occur when the emission of ultrasonic wave into the liquid ^[20].

Pulsed -laser irradiation:

Here the graphite is irradiated with high energy laser pulses. Phase transformation occur from graphite to sp-bonded carbon chains carbine and nanodiamonds has been induced by femtosecond laser pulses on graphite surface ^[20].

Adsorption of drug on nanodiamond:

Most commonly used mechanism for the loading of drug on to the nanodiamond is adsorption. By this mechanism it is easy to create smart environment-and stimuli-responsive nanodiamond drug delivery and release system.

The drug easily was adsorbed as a monolayer onto a 5 nm ND particle. However, the monolayer capacity of ND for a particular drug must be determined in order to gain full advantage, for avoiding excessive loading and potential leaks of the adsorbed drug. Potential leaks of absorbed drugs will be dangerous in case of anticancer chemotherapeutics, it may be toxic to normal and cancerous cells. Knowledge of binding strength of drug to nanodiamond is important, in addition to monolayer capacity in this situation.

In an experiment conducted towards measuring the efficiency on adsorption of drugs (Polymyxin B and Doxorubicin) onto -COOH and –NH₂functionalized nanodiamonds, it was observed that a remarkably high doxorubicin monolayer capacity was achieved with those –NH₂functionalized nanodiamonds and interestingly this same nanodiamonds had the lowest binding strength towards doxorubicin. On the other hand polymyxin B depicted a maximal binding strength because of the change in area of the molecule facing nanodiamond surface due to the change in peptide conformation caused by strong electrostatic interaction between the –NH₂ functionalized nanodiamond and polymyxin B.

Thus from this study it was inferred that when drugs are highly toxic (eg; doxorubicin) should be released from nanodiamonds only after reached at target sites, while minimizing drug release before the ND-drug complex has reached the location, one may have to sacrifice the adsorption capacity in favour of a higher binding strength. In this scenario, -COOH functionalized nanodiamonds will be the preferred choice over –NH₂functionalized nanodiamonds for doxorubicin ^[21].

Surface Modification

Surface uniformity is essential for high surface loading. Surface homogeneity can be achieved by reaction with hydrogen, chlorine and fluorine have been explored to attain surface homogeneity and reactivity enhancement^[22].

Surface functionalization is also helpful to reduce the aggregate size of nanodiamonds. Particle size can be reduced from 15µm to 450nm by functionalizing with long alkyl chains. Surface modification with fluorine reduced the size from 1930 to 160 nm.And with boron there occur a reduction to ~50nm ^[23].

Surfactant dispersed nanodiamonds

On comparing with bare nanodiamonds, surfactant dispersed nanodiamonds have better dispersibility in water. Nanodiamonds nanoparticles possess many hydrophobic areas, which can readily interact with surfactant’s hydrophobic segments through hydrophobic interactions. This exposes the hydrophilic segments of the surfactants to the outside, which makes the surface of nanodiamond clusters hydrophilic. This will enhance their dispersibility in aqueous solution ^[24].

Stability of nanodiamond suspension can also be influenced by their surface charge. The positively charged surface of nanodiamonds will interact with the negative charged surfactants. A surfactant bi-layer can be formed on the nanodiamond surface by the interaction of the hydrophobic alkyl chains of surfactants exposing outside with the hydrophobic segments of other surfactants ^[24].

Nanodiamonds for Bioimaging

In many cases, nanodiamonds are developed for bioimaging as an alternative to fluorescent dyes and quantum dots due to its optical spectroscopic properties. Studies prove that DNA could non-specifically attach onto carboxylated nanodiamonds without any loss in fluorescence. Depending up on the different method of production and size of nanodiamonds, different fluorescent peaks can predominate. Different wavelengths can excite different defects. The most important thing about the nanodiamond fluorescence was stable and didn’t photo bleach, which allows for the development of nanodiamond-based fluorescence markers. Proton beam followed by annealing can be used to create a high concentration of nitrogen defect colour centers (namely, negatively charged nitrogen-vacancy centers). By this fluorescence of nanodiamond can be increased. Nanodiamond’s fluorescence is predominantly emitted from the diamond core and not from the surface ^[25].

Figure 2: Nanodiamonds and drug delivery

Systemic delivery using nanodiamonds

For systemic treatments, nanodiamonds are used as a nanoparticle drug carrier that addresses a multitude of diseases, mainly in late stage malignant cancers. Penetration of leaky vasculature for thorough therapeutic exposure is possible because of their small size and biologically amenable surface. Since nanodiamonds can be introduced by non-surgical method, made them advantageous over the localised implants of introduction ^[26].

Figure 2 shows the drug delivery using nanodiamonds. (a) Endocytosis of the ND–drug complexes, (b) Diffusion of free drug molecules across the cell membrane, (c) Release of drug from nanodiamond, (d) ABC transporter proteins efflux free drug molecules out of the cell and (e) ND–drug complexes remain inside the cell and deliver a steady, lethal dose of the drug to the tumour.

Nanodiamonds for chemotherapeutic delivery

The capabilities of nanodiamonds as promising and cellularly internalized drug carrier were demonstrated with doxorubicin, a clinically relevant antitumour drug used for wide variety of cancer. Doxorubicin was either coated and/or entrapped between nanodiamond aggregates. Most of the chemotherapeutic agents show biological activity against both healthy and cancerous cells. But nanodiamond- mediated ‘shielding’ effect provides innate protection against nonspecific and unwanted processes. The reversible adsorption and desorption of doxorubicin to and from the nanodiamond surface will depend on the surface charge or pH ^[27].

Localised drug delivery using nanodiamonds

Overall systemic drug concentrations can be reduced by focused drug delivery. Localised chemotherapeutic drug delivery shows reduced systemic side effects, improved drug efficacy and biocompatibility, reduces nonspecific elution and inhibit over elution or burst release ^[28].

Localised chemotherapeutic drug delivery

The scope of chemotherapeutics is restricted to the toxicity effects of drug within other organs. Also they produce several problems associated with drug resistance. Due to the low diffusion rate and strong intracellular binding these drugs leaves cancerous cells removed from vessels unharmed. Sequential treatments now try to remove the cells on treatment, both from the periphery and near blood vessels. There by problems produced by perpetual and localised release that associated with drug penetration can be bypassed. While design a localised drug delivery system which should provide basis for controlling dosages for long period of time and maintain a platform for improved biocompatibility and versatility ^[28].

Hybrid nanodiamond-polymer microfilms for localized chemotherapeutic drug delivery.

The nanodiamond mediated slow release capabilities can be translated to the macro scale through the layer of parylene C. This design helps in unidirectional drug release from nanodiamond-drug complexes.

When nanodiamonds added as a constituent, it not only extends the release in a continuous and consistent manner for nearly a month, but also reduced burst release. The advantages of these designs are:

· They provide a stable reservoir of drug.

· They lower the therapeutic release of drug from microfilm and thus extending the active life time of the film.

· The conjugation of nanodiamonds with various disorder specific agents extends the broad applicability of this design in cancer treatments, also with the confines of anti-inflammatory remedies.

In future these device have the potential to be used in microfabrication technology for precise drug placement, delivery, in combinatorial therapeutics and imaging agents ^[28].

Other applications of nanodiamonds:

Nanodiamond had wide range of application due to their small size and presence of high amount of surface atoms. Some major applications/uses of nanodiamonds have been explained in previous sections. Other important applications of nanodiamond can be explained under:

· General applications

· Biomedical applications

General applications:

Skin care:

Nanodiamonds have a unique adsorption capability. Nanodiamonds enhance the effect and penetration of therapeutic moiety and have unique capacity to protect the skin from harmful UV radiation. Its water retaining capacity provide whole day moisturizing effect and to protect the skin from aging. Nanodiamond particles would improve absorption of oils without associated abrasiveness ^[29].

Cosmetics:

Since nanodiamond was non-poisonous in nature, it would be widely used in cosmetics such as dental filling, deodorant, lotion, shampoo, toothpaste, dermal strip, antibiotic and skin cleanser ^[29].

Dental care:

Nanodiamonds were formulated as dental material for filling and reconstruction. It will provide additional mechanical strength and mimics natural enamel when dry, and protect from gum disease ^[29].

Hair and nail care:

Nanodiamonds can be included in shampoo that can improve the contact of unsaturated nanodiamond with biological material and enhance its effects. Nanodiamond in nail polish would improve the durability of the applied nail preparation. A nanodiamond nail polish would last for three to ten time longer than typical nail lacquer formulations ^[29].

Biological applications

Nanodiamond in biomedical applications

Nanodiamond could be applied in biomedical fields as coating materials for implants, surgery tools, etc. due to its hardness, thermal conductivity, chemical inertness, and low cytotoxicity ^[30].

Applications as an excellent sorbent

Almost all life sustaining chemicals can be adsorbed by nanodiamond. Thus, nanodiamond was an excellent adsorbent for amino acids, platelets, proteins, and DNA. Nanodiamonds were used to treat burning skin infections, food poisons, and intestine malfunctions ^[30].

Nanodiamond improves image resolution of MRI

Magnetic resonance imaging (MRI), a non-invasive medical imaging technique that used an intravenous contrast agent to produce detailed images of internal structures in the body. To improve image resolution contrast agents are mainly used in MRI. The coupling of MRI contrast agent to a nanodiamond will improve its contrast efficiency ^[30].

Nanodiamond-insulin administration

The nanodiamond-insulin preparation can be administrated as gels, ointments, and bandages. Since nanodiamonds after extraction tend to cluster naturally and having relatively large surface area, large amounts of insulin can be placed on the nanodiamonds. The insulin releases itself from the nanodiamonds at basic pH^[30].

CONCLUSION:

Nanodiamonds drug delivery system shows a new path to the medical science. As compare to other nanoparticles nanodiamonds have purity, size selectivity, retention of aggregation, colloidal stability and surface functionality. Nanodiamonds have shown great potential to emerge as a platform for delivering drugs into biological systems due to their biocompatibility, high loading capacity and ability to cross cellular membranes. Nanodiamonds are now widely used in cancer treatment. It have unique property to target tumour cell without affecting any normal cell and having acceptable patient compliance. As nanodiamond drug delivery is an emerging and growing concept, it will gaining more attraction by industries and many research scientists due to its wide potential and acceptance.

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Received on 26.06.2016 Accepted on 16.07.2016

Asian J. Pharm. Tech. 2016; 6 (3): 177-182.

DOI: 10.5958/2231-5713.2016.00025.8