APPLICATIONS OF CARBON NANOTUBESFOR DRUG DELIVERYSYSTEMSPRESENTED BY :MURTAZA PUTLIWALAM.PHARM, SGSITS
INTRODUCTION Carbon nanotubes are cylindrical carbon molecules haveNovel properties. They can be about 1/50,000th the thickness of a humanhair. Their unique surface area, stiffness, strength andresilience have led to much excitement in the field ofpharmacy. High Thermal conductivity. Excellent electron emission characterstics. Good candidates for a wide variety of applications,including drug transporters, new therapeutics, deliverysystems and diagnostics.
STRUCTURE OF CARBON NANOTUBES Carbon nanotube (CNT ; also known as buckytubes) is anallotrope of Carbon that is Graphite , in which Carbon atomhave sp2 hybridized state. Nanotubes are cylindrical fullerenes. CNT, which have been constructed with length-to-diameterratio of up to 132,000,000:1. Diameters of the carbon nanotubes have ranging from 2 nm to55 nm. The lengths of CNT are typically several microns. Configurationally it is twodimensional graphene (a singlesheet of graphite ) sheet rolledup with continuous unbrokenhexagonal mesh into acylindrical tube.
GEOMETRY OF CARBON NANOTUBESARMCHAIR ARRANGEMENT ZIGZIG ARRANGEMENTCHIRAL ARRANGEMENT
TYPES OF CARBON NANOTUBES1. SINGLE WALLED NANOTUBES : The diameter of single-wallednanotubes (SWNTs) has approximatelyto 1 nanometer. SWNT are wrapping with layer ofgraphite which one-atom-thick layercalled graphene into a seamlesscylinder. It requires catalyst for their synthesis. Less accumulation in the body.
CONTD…2. MULTIPLE WALLED NANOTUBES : Multi-walled nano tubes (MWNT)consist of multiple rolled layers(concentric tubes) of graphite. It has very complex structure It can be produced without catalyst. Purity of product is high. More chances for accumulation in thebody.
Synthesis of Carbon NanotubeVarious Techniques have been developed to producenanotubes in sizeable quantities, which includs :1. Arc discharge2. Laser ablation3. Chemical vapor deposition (CVD).
Arc Discharge Method• It is the first macroscopicproduction of carbonnanotubes.• Its cost very high and givesyield up to 30 – 90 %• During this process, the carboncontained in the negativeelectrode sublimates becauseof the high dischargetemperatures.• At 100 amps, carbon vaporizesand forms hot plasma.
Chemical Vapor Deposition (CVD) The catalytic vapor phase deposition of carbonwas first reported in 1959 . Most economical method due to cheapest sourceof material i.e Fossil hydrocarbon and gives yieldupto 20-100%•During CVD, a substrate is prepared with a layer ofmetal catalyst particles, most commonly nickel,cobalt, iron, or a combination.•The diameters of the nanotubes that are to begrown are related to the size of the metal particles.•Nanotubes grow at the sites of the metal catalyst;the carbon-containing gas is broken apart at thesurface of the catalyst particle, and the carbon istransported to the edges of the particle, where itforms the nanotubes.
Laser Ablation Method• In the laser ablation process, a pulsed laser vaporizes a graphite targetin a high-temperature reactor .• A water-cooled surface may be included in the system to collect thenanotubes.• The laser ablation method yieldsaround 70% and producesprimarily single-walled carbonnanotubes with a controllablediameter determined by thereaction temperature.• it is more expensive than eitherarc discharge or chemical vapordeposition.
FUNCTIONALIZATION OF CARBON NANOTUBES FORBIOLOGICAL APPLICATIONS:• Raw carbon nanotubes have highly hydrophobicsurfaces, and are not soluble in aqueous solutions.• For biomedical applications, surface chemistry orfunctionalization is required to solubilize CNTsimprove biocompatibility and low toxicity.• Two type of Surface fuctionalization of carbonnanotubes :CovalentNoncovalent• Surface fuctionalization of carbon nanotubes
Covalent fuctionalization• By attaching hydrophilic polymers such as poly ethylene glycol(PEG) to oxidized CNTs, yielding CNT-polymer conjugatesstable in biological environments.• Covalently PEGylated SWNTs synthesized by this strategy forboth In vitro and in vivo applications.Non Covalent fuctionalization• NCF of CNTs can be carried out by coating CNTs with amphiphilicsurfactant molecules or polymers.• NCF of SWNTs by PEGylated phospholipids (PL-PEG) high watersolubility of nanotubes and versatile functionalities Phospholipidsare the major component of cell membranes, and are safe to use inbiological systems.
APPLICATIONS OF CNTsA) Carbon Nanotube Membranes for TransdermalDrug DeliveryB) CNT’S for cancer treatmentC) CNTs for Cardiac Autonomic RegulationD) CNTs for platelet activationE) CNT for tissue regenerationF) Carbon Nanotubes in Drug Delivery: Future Trends
Carbon Nanotube Membranes forTransdermal Drug Delivery• Transdermal systems are attractive methods of drug administrationspecifically when treating patients for drug addiction such as nicotine forsmoking cessation.• Through the use of functionalized carbon nanotube (CNT) membranes,drug delivery to the skin can be controlled by applying a small electricalbias to create a programmable drug delivery system.• a transdermal patch system that can be tailored to an individual’s needswill increase patient compliance as well as provide much more effi cienttherapy.
CNT’S for cancer treatment• CNT’s can be considered as antitumor agents and when incombination with conventional drugs, can significantly enhance theirchemotherapeutic effect with the help of the advanced drug deliverysystem.• It has been reported that Paclitaxel loaded PEG-CNT’s are promisingfor cancer therapeutics.• There are three key features of this nanoscale drug delivery system(DDS):1. Use of functionalized SWCNTs as a biocompatible platform forthe delivery of therapeutic drugs or diagnostics.2. Conjugation of prodrug modules of an anticancer agent that isactivated to its cytotoxic form inside the tumor cells uponinternalization and in situ drug release.3. Attachment of tumor-recognition modules to the nanotubesurface (binding EGFR antibody)
Mechanism by which CNTs enter cells• Incorporation of the drug Either by :– Loading into hollow CNT– Attaching at their outer surface Attachment of the anticancer drug to the outer surface of the CNT canbe through either covalent or noncovalent bonding. CNT with a diameter of 80 nm can be loaded up to 5 million drugmolecules.These are : Passive diffusion of CNTs through the lipid bilayers of the cell membrane Attachment of CNTs to the external cell membrane, resulting in its absorption by thecell using an energy-dependent process, such as Pinocytosis. Endocytosis : Engulfing of CNTs directly by cell.
Summary of Anticancer drug delivery via carbon nanotubesCNTType ofcancer/disease In vivo/in vitro Drug Method of loadingSWCNTs Ovarian cancer NA Gemcitabine Use of external forces to particles in aselected directionSWCNTs Leukemia In vitro Daunorubicin Daunorubicin incubated in phosphate-buffered saline at 37°C for 16 hours withSWCNTsSWCNTs Breast cancer In vitro and inmicePaclitaxel Paclitaxel was modified by succinicanhydride, adding a carboxyl group atthe C-2-OH position SWCNTs withbranched PEG-NH2MWCNTs Human gastriccarcinomaIn vitro and inmiceHCPT(10-hydroxycamptothecin)HCPT is linked to MWCNTs usingdiaminotriethylene glycol (hydrophilicspacer) biocleavable ester linkageSWCNTs Chorio- ,nasopharyngealepidermoidtesticularcarcinomaIn vitro Platinum (IV) The SWCNT-PL-PEG-NH2 was initiallyformed. The SWCNT coated with PEGwas then reacted with the platinum inthe presence of coupling agentsincluding EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride)and NHS
Summary of Anticancer drug delivery via carbon nanotubesCNTType ofcancer/disease In vivo/in vitro Drug Method of loadingSWCNTs52 CervicalcancerIn vitro siRNA SWCNTs reacted with PL-PEG. For theincorporation of disulfide bond, the amide groupof PEG was attached to a heterobifunctionalcrosslinker (sulfo-LC-SPDP). The siRNA was thenattached to SWCNTs via a disulfide bondSWCNTs43 Lymphoma In mice Doxorubicin SWCNTs were sonicated in a solution of PL-PEGfollowed by centrifugation. Excess surfactant wasremoved by filtration and washing. Doxorubicinloading onto pegylated SWCNTs was carried out bymixing.MWCNs51 Breast cancer In vitro Methotrexate Amine-MWCNTs was generated through 1,3-dipolar cycloaddition reaction of zomethineylides.Methotrexate was reacted with f-MWCNTsthrough coupling agents, ie, HATU and DIEA
CNTs for Cardiac AutonomicRegulation• There are single-walled carbon nanotubes used in thecardiac autonomic regulation.• Single-walled carbon nanotubes are portion ofphysicochemical properties with fine component whichmay damage cardiovascular autonomic control thatproved after the study in rats.• SWCNTs may alter the baroreflex function, then affectingthe autonomic cardiovascular control regulation
CNTs for platelet activation• SWCNTs using alongwith platelet P-selectin when injected intoanaesthetized mice, light dye induced thrombus formationwas found and the platelet found to be activated.• Activate blood platelets by inducing extracellular Ca2+ influxthat could be inhibited by calcium channel blockers.
CNT for tissue regeneration• CNTs are combined with polymers such as poly-l-lactide,Polylactide and poly-D,Llactide- coglycolide copolymer whichhave been used as a scaffolds in tissue regeneration.• It can be prepared by mixing solubilized collagen with solutionhaving carboxylated SWCNTs.• Living smooth muscle cell were integrated at the collagenstage to produce cell-seeded collagen carbon nanotubes.
Carbon Nanotubes in Drug Delivery:Recent Trends• f-CNTs have been demonstrated to deliver proteins, nucleic acids, drugs,antibodies and other therapeutics.• Ammonium functionalized CNTs can also be considered very promising vectors forgene-encoding nucleic acids.• CNT’s in Gene Therapy : Gene therapy involves transport of the correct gene byviral or nonviral vectors to the affected area• CNTs seem to represent a very good nonviral vector for gene therapy, because theycan cross the cell membrane by an endocytosis process, and also, because of thefunctionalization of CNTs, the DNA can be transferred without any degradation.• The siRNA delivered via MWCNTs achieved significant inhibition of tumor growth.
Commercially available Carbon Nanotubes• Specification details for carbon nanotubes (SWCT & MWCT)available from Aldrich Materials Science, Sigma-Aldrich Co. LLC.Aldrich Product No. TEM Image Description755710 Single-walled isolated and bundled carbonNanotubes powder2 nm x several µm (length, measured byTEM / SEM) Carbon purity : > 70 % (by TGA)Metal oxide impurity: < 30 % (by TGA) Highspecific surface area (> 1000 m2/g )755133Thin multi-walled (avg. 7~9 walls) carbonnanotubes powder 9.5 nm (diameter, byTEM) x 1.5 µm (length, by TEM)Carbon purity : > 95 % (by TGA)Metal oxide impurity: < 5 % (by TGA)High level of purity.
Aldrich Product No. TEM Image Description755168 Double-walled isolated andbundled carbon nanotubes powder3.5 nm (diameter, by HRTEM) x 1 -10 µm (length, by TEM / SEM)Carbon purity : > 90 % (by TGA)Metal oxide impurity: < 10 % (byTGA) Specific surfacearea: >500 m2/g (by BET)High filed emission characteristicsTransparency755141 Short double-walled isolated andbundled carbon nanotubes powder3.5 nm (diameter, by HRTEM) x 3µm (length, by TEM / SEM)Carbon purity : > 90 % (by TGA)Metal oxide impurity: < 10 % (byTGA) Surface chemistrycharacteristics.755125 Short thin multi-walled (avg. 7~9walls) carbon nanotubes powder9.5 nm (diameter, by TEM) x < 1 µm(length, by TEM) Carbon purity : >95 % (by TGA) Metal oxideimpurity: < 5 % (by TGA) Surfacechemistry characteristics Ease ofdispersability
Why only Carbon Nanotubes out oftremendous Nanocarriers?• CNTs act as promising drug carrier due to their unique chemical, physical,and biological properties, nanoneedle shape, hollow monolithic structure,and their ability to obtain the desired functional groups on their outerlayers.• In case of gene therapy liposomes and microparticles, seem not to be asafer option because of their poor pharmacokinetic profile of theadministered oligonucleotide and conjugated plasmid DNA.• They can be functionalized to be more water-soluble and serum-stable,with low toxicity at the cellular level.• Detection CNTs does not require any type of fluorescent labelling, such asquantum dots. It can be detected directly by TEM or AFM due to theirelectron emission spectroscopy.• Destruction of cancer cells for thermal ablation.• Another application of CNTs for drug delivery is intravenous injection.