Advances in Drug Delivery System: Carbon Nanotubes

 

Syed Zia ul Quasim¹*, Mohd Irfan Ali², Syed Irfan³, Abdul Naveed⁴

¹Department of Pharmaceutics, Deccan School of Pharmacy, Hyderabad.

²Department of Pharmaceutics, Long Island University, New York

³Department of Chemistry, Long Island University, New York

⁴Department of Pharmaceutics, Deccan School of Pharmacy, Hyderabad

 

ABSTRACT:

During last two decades, considerable attention has been given to the development of novel drug delivery system (NDDS). Drug particles in nanometer size range have unique characteristics that can lead to enhance performance in a variety of dosage forms. Nanoparticulate drug delivery system may offer platform of advantages over conventional dosage forms, which includes improve efficacy, reduced toxicity; enhance biodistribution with improved patient compliance. Although fields to develop nanotechnology-based efficient drug delivery systems extend into all therapeutics classes of pharmaceuticals, many therapeutic agents have not been successful because of their limited ability to reach the target tissue. Functionalized carbon Nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine. Carbon Nanotubes (CNTs) have become strongest candidates mainly in the field of biomedical engineering, biotechnology; defense research and pharmaceutical nanotechnology after their discovery in 1991.Ever since, the discovery of CNTs several ways of preparing them has been explored. The introduction and delivery of DNA, proteins, or drug molecules into living cells is important to therapeutics. Inorganic nanomaterials, including nanocrystals, nanotubes, and nanowires, exhibit advanced physical properties promising for various biological applications, including new molecular transporters.

 

 

INTRODUCTION: ^[1]

During last two decades, considerable attention has been given to the development of novel drug delivery system (NDDS). The rational for control drug delivery is to alter the pharmacokinetics and pharmacodynamics of drug substance in order to improve the therapeutic efficacy and safety through the use of novel drug delivery system. Besides more traditional matrix or reservoir drug delivery system, colloidal drug delivery system has gained in popularity. The major colloidal drug delivery system includes liposome and polymeric nanoparticles.¹

 

All drug delivery systems should include continuous regulation of drug levels within the therapeutic range, effective targeted delivery, reduction in the amount of drug needed and, as a consequence, a decrease in toxicity and side effects. Nanotechnology has nearly limitless potential in biomedical applications.²

 

A drug delivery strategy that selectively targets the malignant tumor is much needed. With the focus on these requirements the recent researches shows that Carbon Nanotubes holds good for desired drug delivery systems for the treatment of cancer disease, gene transfer and DNA applications. Functionalized carbon Nanotubes (f-CNTs) are emerging as new tools in the field of nanobiotechnology and nanomedicine.³ Carbon Nanotubes (CNTs) have become strongest candidates mainly in the field of biomedical engineering, biotechnology; defense research and pharmaceutical nanotechnology after their discovery in 1991.These are an important new class of technological materials that have numerous novel and useful properties. They have received very much attention as new classes of nanomaterials .These are the long hollow seamless cylinders (single walled as well as multiwalled carbon Nanotubes) of graphene .The diameter of these tubes in the range of 1-100 nm⁴. These nanotubes are concentric graphitic cylinders closed at either end due to the presence of five-membered rings. The CNTs can be multi-walled with a central tube of nanometric diameter surrounded by graphitie layers separated by ~0.34 nm. Unlike the multiwalled carbon nanotubes (MWNTs), in single walled carbon nanotubes (SWNTs) there is only the tube and no graphitic layers i.e. SWNTs consist of singular graphene cylindrical walls. Ever since, the discovery of CNTs several ways of preparing them has been explored⁵. Solid-state devices in which electrons are confined to two dimensional planes have provided some of the most exciting scientific and technological breakthroughs of the last 50 years.⁶

 

The introduction and delivery of DNA, proteins, or drug molecules into living cells is important to therapeutics. Inorganic nanomaterials, including nanocrystals, nanotubes, and nanowires, exhibit advanced physical properties promising for various biological applications, including new molecular transporters.⁷

 

Classification

Depending on their sheet direction and diameter, CNTs are classified in metallic and semi conducting categories.  Depending on their atomic layer arrangements there are of two types⁸

Ø  Single-walled carbon nanotubes (SWNTs)

The SWNTs are characterized by strong covalent bonding, a unique one dimensional structure, and nanometer size which impart unusual properties to the nanotubes including exceptionally high tensile strength, high resilience and electronic properties ranging from metallic to semi conducting, high current carrying capacity, and high thermal conductivity.⁹

Ø  Multi walled

Multi-walled nanotubes (MWNT) consist of multiple rolled layers (concentric tubes) of graphite. There are two models which can be used to describe the structures of multi-walled nanotubes.

 

i       Russian doll model

ii      Sheets of graphite are arranged in concentric cylinders, single-walled nanotube (SWNT) within a larger single-walled nanotube.

iii     parchment model

iv     A single sheet of graphite is rolled in around itself, resembling a scroll of parchment or a rolled newspaper.

 

Ø  Other Types

a)      Nanobud

b)      Extreme Nanotubes¹⁰

 

Synthesis

Nanotechnology is widely seen as a key technology of the 21st century with a potential wide impact on many key sectors of the industry. Among the various nanomaterials being currently developed carbon nanotubes (CNTs) are often distinguished due to their great properties and the potential benefits they can deliver in many industrial applications (from materials engineering and electronics to medical devices and drug delivery systems). It is therefore essential for industry to ensure a sustainable development of these materials, particularly with respect to Health, Safety and Environment (HSE). CNTs can be synthesized by three conventional methods¹¹

Ø  Arc Vaporization :

This method creates CNTs through arc-vaporization of two carbon rods placed end to end, separated by approximately 1mm, in an enclosure that is usually filled with inert gas at low pressure. A direct current of 50 to 100A, driven by a potential difference of approximately 20 V, creates a high temperature arc discharge between the two electrodes. The arc provides high temperatures which are needed to vaporize carbon atoms into a plasma (>3000°C). ¹²

 

Ø  Laser ablation:

In the laser ablation technique, a high power laser was used to vaporize carbon from a graphite target at high temperature. Both MWNTs and SWNTs can be produced with this technique.  In order to generate SWNTs, metal particles as catalysts must be added to the graphite targets similar to the arc discharge technique. The quantity and quality of produced carbon nanotubes depend on several factors such as the amount and type of catalysts, laser power and wavelength, temperature, pressure, type of inert gas, and the fluid dynamics near the carbon target. The laser is focused onto a carbon targets containing 1.2 % of cobalt/nickel with 98.8 % of graphite composite that is placed in a 1200°C quartz tube furnace under the argon atmosphere (~500 Torr). These conditions were achieved for production of SWNTs in 1996 by Smalley’s group.  In such technique, argon gas carries the vapors from the high temperature chamber into a cooled collector positioned downstream. The nanotubes will self-assemble from carbon vapors and condense on the walls of the flow tube. The diameter distribution of SWNTs from this method varies about 1.0 - 1.6 nm. Carbon nanotubes produced by laser ablation were purer (up to 90 % purity) than those produced in the arc discharge process and have a very narrow distribution of diameters.¹³

 

Ø  Chemical Vapor Deposition (CVD):

CVD is a simple and economic technique for synthesizing CNTs at relatively low temperature and ambient pressure, at the cost of crystallinity. The process involves passing a hydrocarbon vapor (typically for 15-60 minutes) through a tube furnace in which a catalyst material is present at sufficiently high temperature (600-1200°C) to decompose the hydrocarbon. CNTs grow over the catalyst and are collected upon cooling the system to room temperature. In the case of a liquid hydrocarbon (benzene, alcohol, etc.), the liquid is heated in a flask and an inert gas purged through it to carry the vapor into the reaction furnace. When the substrate-catalyst interaction is strong, a CNT grows up with the catalyst particle rooted at its base (known as the ‘base growth model’).

 

When the substrate-catalyst interaction is weak, the catalyst particle is lifted up by the growing CNT and continues to promote CNT growth at its tip (the ‘tip growth model’). Formation of SWNTs or MWNTs is governed by the size of the catalyst particle. Broadly speaking, when the particle size is a few nanometers, SWNTs form, whereas particles a few tens of nanometers wide favor MWNT formation¹⁴

Applications

a.      Molecular transporters or carriers:

Single-walled carbon nanotubes are molecular transporters or carriers with very high optical absorbance in the where biological systems are transparent. This intrinsic property stems from the electronic band structures of nanotubes and is unique among transporters. A laser of λ = 808 nm and can be extended to using light sources spanning the entire 700-1,100-nm range transparent to biosystems for more efficient in vitro excitations of SWNTs with various chiralities to obtain enhanced biological effects. NIR pulses can induce local heating of SWNTs in vitro for endosomal rupture and molecular cargo releasing for reaching intended targets without harming cells, on the other hand, selective killing of cells over expressing tumor markers can be achieved by selective delivery of nanotubes inside the cells via receptor-mediated uptake pathways and NIR-triggered death.

 

The scheme of SWNT functionalization by PEG ligands can be generalized to various ligands or antibodies targeting very specific types of cells. Although the PEG moiety imparts inertness and little nonspecific binding of nanotubes to normal cells, the ligands can recognize cells with complementary receptors for SWNT internalization and subsequent cell destruction by NIR radiation. Specifically functionalized nanotubes could then be a generic “killer” of various types of cancer cells without harming normal cells. Thus, the transporting capabilities of carbon nanotubes combined with suitable functionalization chemistry and the intrinsic optical properties of SWNTs can open up exciting new venues for drug delivery and cancer therapy. An alternative to endocytosis is directly injecting SWNTs into cells in selected tumor regions and then triggering tumor death by NIR radiation.¹⁵

 

b.      Carbon nanotubes for transport and delivery of biological cargos

Both covalently and non-covalently functionalized carbon nanotubes have been shown to have the ability to be internalized inside mammalian cells. This ability has led SWNTs to be utilized as a novel class of transport system that mediate cellular internalization of biological cargos. The internalization of the carbon nanotubes is found to be mediated by the process of endocytosis. Determining the internalization mechanism was key to devising new strategies that allowed the nanotubes to not only carry the cargos inside the cells, but also have the ability to “release” these species.

 

By utilizing a generic functionalization scheme that incorporate a disulfide bond between the SWNTs and a variety of molecules, ranging from simple fluorescent dyes to more complex species such as proteins, antibodies and oligonucleotides. The biological activity of the cargo is preserved following transport and delivery into the cell. This was demonstrated by effective gene silencing by siRNA introduced inside the cells via the nanotubes transporter. Current studies are under way to assess the applications of the SWNT-based transport and delivery system for other biological systems.¹⁶

c.       Polymer coating raises carbon nanotubes potential for drug delivery

Polymer coated carbon nanotubes could find a new use in drug delivery, claim Korean scientists. Sangyong Jon, at Gwangju Institute of Science and Technology, and co-workers designed an amphiphilic polymer coating – that contains both hydrophilic and hydrophobic parts – for carbon nanotubes (CNTs). They found that in vitro the coating made the CNTs dissolve better in water and plasma, and allowed them to conjugate to biomolecules. Both are vital properties for drug delivery applications. Ali Khadem hosseini, who researches biomaterials at Harvard Massachusetts Institute of Technology, Cambridge, US, highlights the potential of this work, ‘researchers are extremely interested in using CNTs for drug delivery; this work takes a step in making this a reality’ but the toxicity associated with CNTs is another major challenge for their future medical applications, but this coating should reduce this problem by making the CNTs more biocompatible¹⁷

 

d.      Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms:

While current treatments for cigarette smoking and opioid addiction do aid in successful abstinence from the individual’s vice, there is great need and room for improvement. The best of smoking cessation therapies reports a mere 19% success after one year, while only 50% of individuals who enter clinics for opioid addiction remain for the duration of the treatment, of which 65% return to using within 4 weeks. Clearly, a therapy that better controls cravings or abates withdrawal symptoms to decrease the likelihood of relapse is needed. Carbon nanotube (CNT) membranes present the opportunity to create a transdermal patch that can vary its rate of delivery throughout its application to the skin to attain therapeutic plasma levels and plasma profiles of a specific drug¹⁸

 

e.       Encapsulation of the Anticancer Drug Cisplatin into Nanotubes:

Nanotubes offer a number of advantages which suggest that they may provide an improved result. Namely, they have a larger inner volume which allows more drug molecules to be encapsulated, and they have distinct inner and outer surfaces for functionalization. In addition, the volume and surfaces of the nanotube are more readily accessible since the end caps can be easily removed. Both nanoparticles and nanotubes have been shown to be readily taken up by cells.Nanotubes have been found to enter cell nuclei suggesting another advantage in that they may be useful in gene therapy. The general proposed drug delivery process using nanotubes nanotube carrier such that prior to delivery it is energetically favorable for the drug molecule to be encapsulated, and once inside the desired cell it is energetically favorable to be ejected.

 

Thus, the contents are deposited to the target site. Understanding the encapsulation and expulsion of drug molecules from nanocarriers is vital for the development of nanoscale drug delivery.Cisplatin is a platinum based anticancer drug which is used to treat a wide range of tumors, despite its adverse side effects. It is expected that this form of targeted nanoscale drug delivery will significantly reduce these adverse side effects. the most ideal delivery capsule in terms of minimizing the amount of material required for encapsulation, thus providing the least toxicity. This technique, used to represent the encapsulation of cisplatin entering carbon, boron nitride, boron carbide and silicon nanotubes, can be extended to any number of drug molecules or alternative nanotube materials¹⁹

 

f.       Conjugation of Amphotericin B to Carbon Nanotubes via  Amide-Functionalization for Drug Delivery:

Targeted drug delivery is the most important goal of pharmaceutical research which is to delivery therapeutic molecules to targeted cells in a safe and efficient manner. Nanotechnology has nearly limitless potential in biomedical applications. Nanoparticles, among all available drug carriers gain more attractive attention; since they can be so manipulated that remains in circulation system to reach the diseased site and can penetrate through the cell membrane. Above all, carbon nanotubes possess the capacity of penetrating the blood-brain barrier without causing the death of a living cell or without inflicting other damage.

 

In order to modify carbon nanotubes which increase their biocompatibility and solubility profile, different functionalization approaches will apply to CNTs. Therefore, functionalization of carbon nanotubes is a key step for further their application. The oxidative reactions are widely employed for chemical modification of CNTs which generate carboxylic groups to the tips and defect sites of CNTs. These functional groups can further attached to other reactive groups or biological molecules such as drugs and used to deliver their cargos to cells and organs.

 

As a therapeutic molecule antibiotic amphotericin B, which is used in the treatment of fungal infections, can be delivered by the means of carbon nanotubes. CNT is oxidized using strong acids, resulting in the reduction of their length while generating carboxylic groups, which increase their dispersibility in aqueous solutions. According to the results the best length and the loading of the carbon nanotubes was achieved for 8 h as they exhibited the most convenient length and loading. Thus, the process can guarantee homogenous attachment of Drug molecule onto carbonnanotubes.As evidence, UV/vis studies showed that Amphotericin B molecules successfully conjugated to the surface of amide functionalized Carbon nanotubes. This approach provides an efficient method to conjugate therapeutic proteins like Amphotericin B molecules to Carbon nanotubes for further delivery purposes²⁰

 

 

g.      Detection of Toxic Organophosphoric Compounds:

Organophosphoric compounds are generally used in insecticides, pesticides .These chemicals are CNS affecting by inhibiting acetylcholine esterase which functions on acetylcholine neurotransmitters. To monitor these toxic compounds, the electrochemical detection is necessary. Carbon Nanotubes are the electrode materials has the possibility of promoting electron transfer reaction at enzymes immobilization. Acetylcholine esterase is immobilized on Nanotubes surface and catalyses hydrolysis if thiocholine ester, forms thiocholine and oxidation of thiocholine can be detected by electrochemical techniques. On Organophosphoric compounds action acetylcholine esterase catalytic property become reduced and simultaneously the oxidation of thiocholine inhibited and this can be detected by amperometric analysis using CNTs electrode.

h.      Detection of Alkylating Agents Containing Sulphur And Nitrogen:

Alkylating agents (nitrogen mustards; ethylenimes ;alkylsulphonates ;triazenes; piprazenes ;nitrosureas.) can be detected by DNA sensing as the biological recognition element which could have numerous applications. To improve the sensitivity aligned CNTs should be used as nanoelectrodes array for DNA recognition

 

i.        Detection of Toxic Proteins and Micro Organisms:

The mechanism of CNTs using as biosensors devices can be explained by the change in electrical signals, the CNTs can be used as a measuring platform for various toxic proteins which will immobilized on the CNTs by both covalent and non covalent means. This immobilization properties of antibodies by means of sensing improves their activity in antigen-antibodies biosensors. Scanning electron microscope (SEM) and electrochemical chemiluminescence (ECL) can be used to test the bonds of proteins with antibodies on CNTs platform. Finally the detection can be done by integrating these sensor tips to a single conditioning and processing circuits and measurements analysis of conductance and electrical signals obtained in presence of toxic proteins²¹

 

CONCLUSION:

All drug delivery systems should include continuous regulation of drug levels within the therapeutic range, effective targeted delivery, reduction in the amount of drug needed and, as a consequence, a decrease in toxicity and side effects. Nanotechnology is widely seen as a key technology of the 21st century with a potential wide impact on many key sectors of the industry.

 

Among the various nanomaterials being currently developed carbon nanotubes (CNTs) are often distinguished due to their great properties and there potential benefits, they can deliver in many industrial applications (from materials engineering and electronics to medical devices and drug delivery systems).

 

CNTs drug delivery system may offer platform of advantages over conventional dosage forms, which includes improve efficacy, reduced toxicity, enhance bio-distribution with improved patient compliance. CNTs are an important new class of technological materials that have numerous novel and useful properties.

 

They have unique structure, and nanometer size which impart unusual properties to the nanotubes including exceptionally high tensile strength, high resilience and electronic properties ranging from metallic to semi conducting, they can be readily functionalized and several studies on the use of Carbon Nanotubes as versatile substances for drug delivery and imaging of disease processes have been reported, suggesting that Carbon Nanotubes may have a place in the armamentarium for treatment and monitoring of cancer, infection, and other disease conditions. Apart from their use in cancer treatment, they are also used as biological carriers. Carbon nanotube (CNT) membranes also present the opportunity to create a transdermal patch that can vary its rate of delivery throughout its application to the skin to attain therapeutic plasma levels and plasma profiles of a specific drug^, a platinum based anticancer drug, cisplatin which is used to treat a wide range of tumors, despite its adverse side effects.

 

They also show very good adsorption properties which helps in the detection of various chemicals, toxic agents. Polymer coated carbon nanotubes could find a new use in drug delivery due to their amphiphilic nature, It is expected that this form of targeted nanoscale drug delivery will significantly reduce toxicity associated with CNTs for their future medical applications, this coating will reduce this problem by making the CNTs more biocompatible. In a view of these varied applications of CNTs represents a new, emerging class of delivery systems for the transport and translocation of drug molecules into different types of mammalian cells. Although CNT conjugates displayed show not much cytotoxicity in vitro, for further development, it will be important area of advance drug delivery system to be explored.

 

REFERENCE:

1.       J. C. Rathi et al., Formulation and Evaluation of Lamivudine Loaded Polymethacrylic Acid Nanoparticles, International Journal of PharmTech Research Vol.1, No.3, July-Sept 2009, 411-415.

2.       Manouchehr Vossoughi1 et al., Conjugation of Amphotericin B to Carbon Nanotubes via Amide-Functionalization for Drug Delivery Applications, Engineering Letters Vol 17, 19 November 2009, 4-12.

3.       Smriti Khatri et al., Carbon nanotubes in pharmaceutical nanotechnology: An introduction to future drug delivery system, Journal of Chemical and Pharmaceutical Research Vol 2(1), 2010, 444-457.

4.       K. S. Rathore et al., Bucky balls: A novel drug delivery system, Journal of Chemical and Pharmaceutical Research, Vol 2(2) 2010, 240-248.

5.       S.karthikeyan*, P. Mahalingam and M. Karthik, Large Scale Synthesis of Carbon Nanotubes, E-Journal of Chemistry Vol 6(1), September 2009, 1-12.

6.       Paul  McEuen, Single-wall carbon nanotubes, physics world, Vol 1, Jun 2000, 31-38.

7.       Nadine Wong Shi Kam et al. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction, Proceedings of the National Academy of Sciences of the United States of America, Vol 102, Aug 16 2005, 11600-11605.

8.       Smriti Khatri et al., Carbon nanotubes in pharmaceutical nanotechnology: An introduction to future drug delivery system, Journal of Chemical and Pharmaceutical Research Vol 2(1), 2010, 444-457.

9.       Paul McEuen, Single-wall carbon nanotubes, physics world, Vol 1, Jun 2000, 31-38.

10.     Hae, Han Gi, Kumar, Satish, Rigid Rod Polymeric Fibers, Journal of Applied Polymer Science, Vol 100 (1), 791–802.

11.     Producers Association of Carbon nanoTubes in Europe (PACTE)- Code of Conduct for the Production and Use of Carbon Nanotubes, Version 1.0, 2008-03-04, p.g 1-3.

12.     S.karthikeyan*, P. Mahalingam and M. Karthik, Large Scale Synthesis of Carbon Nanotubes, E-Journal of Chemistry Vol 6(1), September 2009, 1-12.

13.     A. Thess et al, Crystalline ropes of metallic carbon nanotubes, Science, 273, 1996, 483–487.

14.     W. S. Mcbride, Synthesis of Carbon Nanotube by Chemical Vapor Deposition, Undergraduate Degree Thesis, College of William and Marry in Virginia, Wil-liamsburg, 2001.

15.     Nadine Wong Shi Kam, Michael O’Connell et al. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction, proceedings of national academy of science of the united states of America, vol 102 no. 33, August 2005, 11600-11605.

16.     Nadine Wong Shi Kam et al, Single walled carbon nanotubes for transport and delivery of biological cargos, physica status solidi (b) 243, No. 13,October 2006, 3561-3566.

17.     Chemical Science, Carbon nanotubes wear coats to deliver drugs, Volume 5, June 2008, C41–C48.

18.     Caroline L. Strasinger et al, Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms, Substance Abuse: Research and Treatment, Vol 3, 2009, 31-39.

19.     T. A. Hilder_ J. M. Hilly, Encapsulation of the Anticancer Drug Cisplatin into Nanotubes International, Conference on Nanoscience and Nanotechnology, ICONN 2008, Melbourne, February 2008, 107-112.

20.     Manouchehr Vossoughi1 et al, Conjugation of Amphotericin B to Carbon Nanotubes via Amide-Functionalization for Drug Delivery Applications, Engineering Letters, Vol 17, November 2009, 4-12.

21.     Smriti Khatri et al, Carbon Nanotubes in Pharmaceutical Nanotechnology: An introduction to Future Drug Delivery System, Journal of Chemical and Pharmaceutical Research, Vol 2(1), 2009, 400-420.

 

 

Received on 11.12.2012       Modified on 15.12.2012

Accepted on 18.12.2012      © RJPT All right reserved