diamondoids as molecular building blocks for ......(2). university of illinois at chicago (m/c 063),...

Diamondoids as Molecular Building Blocks for Nanotechnology, Drug Targeting and Gene Delivery

Hamid Ramezani (1) and G. Ali Mansoori(2)

(1). Mashhad University of Medical Sciences, Mashhad, Iran, [email protected]

(2). University of Illinois at Chicago (M/C 063), Chicago, IL 60607-7052, [email protected]

ABSTRACT

In this report physical and chemical properties of diamondoids, which are organic compounds with unique structures and properties, as the molecular building blocks (MBBs) for nanotechnology are investigated. It is reported that some of their derivatives have been used as antiviral drugs for many years. Due to their flexible chemistry, their exploitations to design drug delivery and drug targeting are examined. Some methods and concepts in their role as MMBs in formation of nanostructures including various aspects of self-assembly are introduced. Those include self-assembly using solid surface, immobilization techniques molecules on a solid support, DNA directed self-assembly, self-assembly in liquid medium, and host-guest chemistry approach. The applications of diamondoids in host-gust chemistry to construct molecular receptors by self-assembly process is presented. It is concluded that diamondoids are one of the best candidates for molecular building blocks (MBBs) in molecular nanotechnology to design nanostructures with predetermined physicochemical properties.

Keywords: Adamantane, Diamondoids, Drug delivery, Drug targeting, Host-guest chemistry, Molecular building block, Nanostructures, Nanotechnology, Self-assembly, Self-replication.

Molecular Building Blocks for NanotechnologyFrom Diamondoids to Nanoscale Materials and Applications

GA Mansoori, TF George, L Assoufid, and G Zhang (Ed's) Topics in Applied Physics, Volume 109, Pages 44-71, 2007 Springer

https://www.springer.com/us/book/9780387399379

Chapter 3 of

Preprint

DOI: http://dx.doi.org/10.1007/978-0-387-39938-6

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1. Introduction

1.1 Diamondoids

Diamondoids are cage-like saturated hydrocarbons. They can be considered to consist of fused chair form cyclohexane rings. They are one of the components which deposit in gas and oil pipelines and were isolated from crude oil in 1933 for the first time [1,2]. They are called "diamondoid" because they can be assumed as repeating units of the diamond. The most famous member of this group, Admantane, is a tricyclic saturated hydrocarbon (tricyclo [3.3.1.1]decane). The common formula for this group is C4n+6H4n +12 where n=1 is admantane, n=2 is diamantane and so on (Fig. 1.). The first three compounds of this group do not possess isomeric forms while from n≥4 the number of isomers would significantly increase. Diamondoids can be divided into two major clusters based upon their size: lower diamondoids (1-2 nm in diameter) and higher diamondoids (>2nm in diameter). Escobedo et al [3] and Vasquez and Mansoori [4] succeded in separating, measuring the concentrations and identifying diamondoids from petrolum crude oils. Recently Dahl et al have identified higher diamondoids, from n=4 to n=11, and their isomers as the building blocks for nanotechnology [5].

1.2 Some Physical and Chemical Properties diamondoids show unique properties due to their exceptional atomic arrangements. These compounds are chemically and thermally stable and strain-free and these can make them have a high melting point in comparison with other hydrocarbons. For instance, the m.p. of admantane has been estimated to be in the range of 266-268°C and for diamantane it is 241-243°C. Such high melting points of diamondoids have caused arterial blockage in oil wells, transport pipelines and processing equipment during production, transportation and processing of diamondoids-containing petroleum and natural gas [3]. One may also exploite the large difference of diamondoids and other petroleum fractions for isolating of diamondoids from petroleum [1, 5]. Many of diamondoids can be brought to macroscopic crystalline forms with some special properties. For example, in it’s crystalline lattice, pyramidal [1(2, 3)4] pentamantane has a large void in comparison with similar crystals. Although it has a diamond-like macroscopic structure it possesses weak intermolecular van der waals forces involved in forming crystalline lattice and no intermolecular covalent bonds [5, 6].

The crystalline structure of 1,3,5,7-tetracarboxy adamantane is formed via carboxyl hydrogen bonds of each molecule with four tetrahedral nearest-neighbors. The similar structure in 1,3,5,7- tetraiodoadamantane crystal would be formed by I…I interactions. In 1,3,5,7-tetrahydroxyadamantane, the hydrogen bonds of hydroxyl groups produce a crystalline structure similar to inorganic compounds, like CsCl, lattice [7] (Fig. 2.).

Presence of chirality is another important feature in many derivatives of diamondoids. Such a chirality among the unsubstituted diamondoids occurs first of all in tetramantane [5]. Recently, Masatoshi Shibuya et al. have represented two convenient methods for synthesis of enantiomeric adamantane derivatives [8].

The vast number of structural isomers and streoisomers is another property of diamondoids. For instance, octamantane possesses hundereds of isomers in five molecular weight classes. The octamantane class with formula C34 H38 and molecular weight 446 has 18 chiral and achiral isomeric structures. Furthermore, there are unique and great geometric diversity with these isomers. For example

H. Ramezani and G.A. MansooriDiamondoids as Molecular Building Blocks for Nanotechnology, Drug Targeting and Gene Delivery

Ch. 3, Mol. Build. Blocks for Nanotechnology, Topics in Applied Physics109: 44-71, 2007, Springer

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rod-shaped diamondoids (which the shortest one is 1.0 nm), disc-shaped diamondoids and screw-shaped ones (with different helical pitches and diameters) have been recognized [5].

Diamondoids possess great capability for derivatization. This matter is of importance for reaching to suitable molecular geometries. These molecules are substantially hydrophobic and their solubility in organic solvents are a function of that (admantane’s solubility in THF is higher than in other organic solvents [9]).Using derivatization, it is possible to alter their solubility. Functionalization by different groups can produce appropriate reactants for desired reactions. Strain-free structure of diamondoids gives them high molecular rigidity. High density, low surface energy, oxidation stability are some other diamodoids properties. Producing diamondoids via synthetic method is not convenient because of unique structural properties and specially their thermal stability.

Besides natural gas and oil reservoirs as the source for diamondoids one may produce them through synthesis starting with adamantane. Outstanding successes have been achieved in synthesis of admantane and and higher diamondoids. Admantane was synthesized in 1941 for the first time [2], however, the yield was very low. The new methods have been developed since that time and the yield has been increased to 60% [10]. The usage of zeolites as a catalyst in synthesis of admantane has been investigated and different types of zeolites have been tested for achieving better catalyst activity and selectivity in adamantane formation reactions [2].

1.2 Applications

Since the main purpose of this report is description of potentials and applicable aspects of diamondoids utilization as MBBs in nanotechnology and drug targeting, this subject would be discussed subsequently in details. But a summary of main diamondoids applications will be brought in this section in order to obtain deeper and comprehensive insight to these hydrocarbons. Sui generis properties of diamondoids, some of which were already enumerated, have provoked an extensive range of inquiries in different fields of science and technology. In pharmacology, two adamantane derivatives, Amantadine (1-adamantaneamine hydrochloride) and Rimantadine (α-methyl-1-adamatane methylamine hydrochloride) have been well-known because of their antiviral activity (Fig. 3.).The main indication of these drugs is prophylaxis and treatment of influenza A virus infections and they are also used in treatment of parkinsonism and inhibition of hepatitis C virus (HCV) [11]. Memantine (1-amino-3,5- dimethyladamantane) has been reported effective in slowing the progression of Alzheimer's Disease [11].

Extensive investigations have been performed related to synthesis of new adamantane derivatives with better therapeutic actions and less adverse effects. For example, it has been proved that adamantylaminopyrimidines and -pyridines are strong stimulants of tumor necrosis factor (TNF-α) [12], or 1,6-diaminodiamantane possesses an antitumor and antibacterial activity [13]. Many derivatives of aminoadamantanes have antiviral activity and 3-(2-adamantyl) pyrolidines with two pharmacophoric amine groups have antiviral activity against influenza A virus [14].

Some derivatives of adamantane with antagonist effects have been also synthesized. For instance, monocationic and dicationic adamantane derivatives block the AMPA and NMDA receptors [15,16,17] and also 5-HT3 receptors [18].



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Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists (Bradykinin antagonists [19] and vasopressin receptor antagonists are two examples).

Diamondoids are one of the best candidates for molecular building blocks (MBBs) to construct nanostructures in molecular nanotechnology [20]. In this field, it is potentially one of the diamondoids features, the possibility of introducing six linking groups to adamantane and thus forming a three dimensional consistent structure, which has attracted attention. Taking into account this fact that MBBs with three linking groups, like graphite, can only produce planar or tubular structures and MBBs with four linking groups can form three dimensional diamond lattice, MBBs with five linking groups can create 3-dimensional solids and hexagonal planes and ultimately MBBs with six linking groups, like adamantane and buckyballs (C60) can construct cubic structures [21].

Such a MBBs have many applications in nanotechnology and they are of great interest in designing shape-targeted nanostructures, nanodevices, molecular machines [20, 22, 23], nanorobots and synthesis of supramolecules with manipulated architecture. As an illustration the possibility of using diamondoids in designing an artificial red blood cell, called "Respirocyte" it has been studied which has the ability to transfer respiratory gases and glucose [24,25,26,20].

Diamondoids have noticeable electronic properties. In fact, they are H-terminated diamond and the only semiconductors which show a negative electron affinity [5].

Diamondoids can be used in self-assembly, positional assembly, nanofabrication and many other important methods in nanotechnology. Also they have found applications in drug delivery and targeting systems and pharmacophore-based drug design as it was already mentioned. Furthermore, they have the potential to be utilized in rational design of multifunctional drug systems and drug carriers. In host-guest chemistry and combinatorial chemistry, there is plenty of room for working with diamondoids. The other potential application of diamondoids is in designing molecular capsules and cages for drug delivery which will be discussed in later sections of this report.

Diamondoids, specially adamantane, it's derivatives and diamantane, can be used for improvement of thermal stability and other physicochemical properties of polymers and preparation of thermosetting resins which are stable at high temperatures. For example diethynyl diamantane has been utilized for such an application [13]. As another example, adamantyl-substituted poly(m-phenylene) is synthesized starting with 1,3-dichloro-5- (1- adamantyl) benzene monomers (Fig. 4.) and it is showen to have a high degree of polymerization and it is going to be decomposed around 350°C[27].

In another study, introducing adamantyl group to the poly (etherimide) structure caused polymer glass transition temperature, Tg , and solubility enhancement in some solvents like chloroform and aprotic solvents [28]. Introducing bulky side-chains which contains adamantyl group to poly(p-phenylenevinylene) (PPV), a semiconducting conjugated polymer ( in short known as PPV polymer) elicits diminution of intrachain interactions and thus, aggregation quenching would be reduced and polymer photoluminescence properties would be improved [29]. Substitution of the bulky adamantly group on the C(10) position of the biliverdin pigments structure, would lead to the distortion of helical conformation and hence, the pigment color would shift from blue to red [30].



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Adamantane can be used in molecular studies and preparation of fluorescent molecular probes [31]. Because of it's incomparable geometric structure, the adamantane core can impede interactions of fluorophore groups and self-quenching would diminish due to steric hinderance. Hence, mutual quenching would be diminished and it becomes possible to introduce several fluorescent groups to the same molecular probe in order to amplify the signals. Figure 5 shows the general scheme of an adamantane molecule with three fluorophore groups (F1) and a targeting group for attachment of biomolecules. Such a molecular probe can be very competent in DNA probing and specially in fluorescent-in-situ hybridization (FISH) diagnostics [32].

2. Drug Delivery, Drug Targeting and Nanotechnology

More than half of drugs are hydrophobe and hence they are poorly soluble in aqueous media of bloodstream. Moreover, many of them are sensitive molecules which can be decomposed pending the absorption process (like protein, nucleic acid or hormone drugs) or being cleared from the plasma by excretory mechanisms and specially metabolism after absorption. Dosage control particularly along with considering the rout of administration is of great importance. Most of drugs have some side effects on the other organs as well as therapeutic effects on their target organ and it should be taken into account in dosage. Briefly, drug delivery systems are developed for improvement of solubility, stability, half-time of drug presence in blood circulation, bioavailability and dosage control of drugs. Carriers in these systems can be particulate, soluble or cellular [33]. There are many particulate systems like liposomes, polymeric micelles, nanoparticles, molecular cages, microspheres (30-200 µ), lipoproteins, plasma proteins and etc.

Among these, nanoparticulate systems use carriers smaller than 1 µ (and usually smaller than 500 nm). Nanoparticles can be polymeric or a molecular cage (like cyclodextrins). Although drug delivery systems for many drugs, meet the qualifications for delivering drugs to the body but that is not the ultimate goal. This is because, if the drug doesn't accumulate in it's specific site of action it won't be able to produce the desired therapeutic effects, even in such a high concentration that exceeds its toxic level. On the other hand, many of drugs present a wonderful effectiveness outside the body (in vitro situation), like cytotoxic, antitumor or CNS drugs, but the main challenge is providing effective dose in the site of action in vivo without any significant adverse effects on the other organs. Thus, the concept of "Drug Targeting" becomes a necessity. In site-specific drug delivery there are many methods which exploit organ-specific strategies but overall, these methods can be divided into three classes: biological, chemical and physicochemical approaches [34]. The other classification of targeting methods is active and passive targeting [35]. In passive type nanoparticulate carrier is absorbed under a physiologic mechanism (for example via phagocytosis by mononuclear cells) and leads to incorporated drug uptake, while in active type it is necessary to utilize a specific targeting sequence, like antibody fragments or a specific ligand, to enhance the drug accumulation in the target site.

Targeting can be considered in three levels: 1-Organ or tissue. 2- Cell. 3- Inside the cell. Intracellular targeting is the most complicated one and it's well- known example is gene delivery especially when the aim is gene delivery to the nucleus. The most important drug uptake mechanism (if the drug can not enter the cell or nucleus by passive ways like diffusion) is endocytosis. In this process some vesicles are formed from the lipoprotein membrane of the cell (endosome). If it is desired to deliver a drug to a specific organelle or cytoplasmic receptors (like steroidal hormones receptors), the



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drug must be released from the endosomes to the cytoplasm and it is done by endosomal membrane-lytic agents.

Endosomes can deliver their content to various organelles like lysosome or nucleus (Fig. 6.). Endosomal trafficking patterns within the cell are very complex and are directed by glycoside recognition sequences. Our knowledge about the details of this trafficing is rather small.

Mitochondria can also be an important intracellular target as well as lysosome and nucleus. Although just 37 genes are expressed in mitochondrial genum [36], the role of this organelle in intracellular calcium modulation, apoptosis and free-radicals production has been established [33].The cationic carrier utilization for mitochondrial DNA and gene delivery has been studied [37].

One of the major aims in genetherapy is control of gene expression at the translation level because translation process occurs in the cytoplasm and ribosomes. The mRAN targeting of an individual gene (for instance an activated oncogene) can prevent and modify translation of that gene. It is one of the mechanisms of peptide nucleic acids (PNAs) action. These stable macromolecules consist of two complementary sequences which can be specifically hybridized to a RNA or DNA strand. Furthermore, the PNAs affinity for fitting to the DNA major grooves and formation of different kinds of duplex and triplex is very high and such an affinity can be exploited to control gene expression at transcription level and also gene targeting at DNA level (anti gene activity). Specific targeting of some mRNAs related to oncogenes would be possible by PNAs [38]. It is believed that nuclear trafficking of some transcription factors can also involve in control of gene expression [36] and by impeding transfer of transcription factors from cytoplasm to nucleus, gene expression can be controlled [39].

Designing new drugs and invention of novel and effective methods for gene targeting, can be achieved by enhancing our understanding from nucleocytoplasmic transport mechanisms [39, 40]. It is necessary to mention that appropriate carriers should be used for gene delivery to the cells (first or second targeting level). Since the genes and nucleoproteins are very sensitive and unstable, they would be readily decomposed in the bloodstream. Also, their small uptake by cells significantly decreases their efficacy. Thus, carriers are unavoidable for such drugs. Gene vectors can be divided in two groups: viral and non-viral. Although viral vectors [41] have been more effective so far, they are always under question because viral infection risk also exists. So far, non-viral vectors have been mostly polymeric [42,43,44] but their efficiency has not been reached to the desired level yet.

A site-specific drug delivery system mainly comprises the following four parts: 1- Drug or therapeutic agent.2- Carrier which is necessary due to enumerated reasons. It is attached to the drug directly (for

example via conjugation) or via a linker/spacer and it may surround the drug through encapsulation or physical entrapment (like liposomes).

3- Spacer or linker which is a weak but stable intermediate between drug and carrier. This partwould be decomposed by one of the medium agents (like enzyme or acidic pH) after reaching to the favored site and drug releases from the system. Peptidic sequences (amid bonds) or ester bonds are usually used for linking. However, in some systems there is no need to use linkers.

4- Targeting sequence which induces accumulation of drug in a specific site and can consist ofspecific antibody fragments for surface markers of an individual tissue or cell. It can also involve specific ligands for some receptors. In some cases like nanocapsules or polymeric micelles (10-100



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nm) there is a central core which absorbs the drug and then, an outer layer enfolds such a core [44]. This layer can facilitate modification of the nanoparticle surface as well as providing more stability.

Receptor targeting is another method in drug targeting. The targeting sequence is a specific ligand for a receptor which is exclusively expressed on the desirable cell surface. However, finding such receptors is difficult but it is one of the major methods in drug delivery for drug transport through the membranes. The most important known mechanism in this case is receptor-mediated endocytosis (RME). Glycosides and their cholesterol or palmitoyl derivatives have been examined as a targeting tool in "Glycotargeting". Some applications for polysaccharide anchored liposomes have been mentioned [45]. There is an opinion accounts lectin or lectin-like receptors involved in endocytosis [46].

Brain drug delivery is another example. Endothelial cells which pave the interior surface of the brain vessels constitute tight junctions which are not permeable to the most of molecules, especially hydrophilic ones. Such a blood-brain barrier (BBB) has produced a serious problem in delivery and penetration of drugs which are effective on central nervous system (CNS).

Utilization of brain nutrient transporters (like amino acids and different kinds of carbohydrates), insulin, transferrin, LDL receptor , exploitation of transcoytosis and receptor-mediated endocytosis mechanisms are some of interesting and major strategies in brain targeting. Chimeric peptides can be used in this case [33]. Chimeric peptides consist of a drug, a carrier (which is a monoclonal antibody and also has a targeting role) and a linker like a (strept)avidin-biotin conjugate. The linker doesn’t release it’s drug content when it is in the plasma but after passing BBB it does. Using endogenic ligands like transferrin or insulin probably leads to disturbing their physiologic balance in the blood circulation. Inasmuch as chimeric peptide system is wholly peptidic, it’s stability in bloodstream and their oral administration are somehow problematic. Polymeric carriers can be used for drug delivery to the brain. Poly (butylcyanoacrylate) nanoparticles are the best example for this purpose [47].

Regarding intracellular targeting, it should be noted that it is necessary to use intracellular targeting sequences for each organelle. For instance, signal-mediated nuclear import can be used for nuclear targeting. In this case, some amino acid sequences called "Nuclear localization signals" (NLSs) are able to facilitate active import of different agents to the nucleus. Mitochondrial targeting also demands mitochondrial localization signals. An effective method for production of targeting ligands is phage display technology/libraries [33]. Another important point which should be regarded is nanoparticle surface properties. A nanoparticle is expected to be biocompatible. Bearing surface charge and hydrophilicity can improve the solubility and also conduce to decrease of phagocytosis by mononuclear cells. Thus, accumulation of nanoparticles in undesirable organs especially the liver and spleen (in some instances which these organs and mononuclear cells are not the aim of targeting) would be reduced. Furthermore, increasing our intimacy in regard to substantial properties of colloidal systems and means of their adjustments can help us to invent and design new targeting methods (For example magnetic targeting via magnetic nanoparticles and ferrofluids [48, 49]).

Although many outstanding improvements have been occurred in drug delivery and targeting technology (at least in research stages) during the last several years but the mature and perfect instance of "magic bullet" which was first posed by Paul Ehrlich in the late 19th century for delivering drugs and other biomolecules to the cells and tissues has not been materialized yet .



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Nanotechnology attempts to perceive fundamental principals which are dominant on substances at the nanometer scale (like intermolecular interactions and quantum behavior of materials) and thus paves the way for creating and construction of novel molecular structures which are not accessible by conventional methods. In fact, using such substantial principals would lead to foundation of a molecular architecture and makes molecular manipulation available for scientists to manipulate supramolecules in such a rational and directed way. However, the molecular designing and instituting changes at nanometer scale has been using more than two decades in drug delivery (for example utilization of plasma proteins like albumin and their modification for drug delivery). However, the ultimate goal in nanotechnology that is gaining control over molecular universe has not been achieved yet. Some nanoelectronic techniques like lithography, etching, microfabrication, nanoelectromechanical systems, thin film deposition and many other ones have been exploited to produce controlled release drug delivery systems. Different types of diagnostic kits, DNA microchips and microarrays have been produced in order to increase diagnosis and treatment efficiency. The construction of nanosensors [50], silicon microneedles, biocapsules, etc are being developed increasingly [51]. Designing self-regulated controlled release systems and magnetic, ultrasound or thermal triggered release systems have been investigating since many years ago [52, 53, 54]. Invention of novel methods and success in creating effective drug delivery and targeting systems completely depends on having a great intimacy about target sites, therapeutic agents, vector or carrier properties and drug transport mechanisms in the body. Designing such sophisticated processes would not had lead to outstanding consequences without multidisciplinary cooperation. It is unavoidable to use nanoscience in each step of drug targeting systems development. Drug delivery and targeting technology will indeed inspire a deep impact on nanotechnology growth.

3. Towards Nanostructures; Some Methods and Concepts

Nanofabrication of nanostructures demands appropriate methods and molecular building blocks (MBBs).Vast number of materials have been suggested for this purpose like biomolecular and organic MBBs. MBBs properties will not be discussed here but it is mentioned that the organic MBBs are of more interest in nanodevices fabrication and bioapplications due to their flexible chemistry and also biomolecules (for instance DNA double helices) for their biocompatibility. Diamondoids, fullerene, graphite and carbon nanotubes are some examples of organic MBBs [23].

As with regard to nanoarchitechture two distinct approaches have been prospsed [21, 55]: 1-Positional or robotic assembly. 2- Self-assembly.

Positional assembly utilizes a robotic arm (like an AFM tip) to control steric position of building blocks. The major difficulty in positional assembly is overcoming on thermal noises which can cause positional uncertainty. This problem can be solved to some extant by using stiff and rigid MBBs (like diamondoids) and also lowering the temperature. Some assemblers with said robotic arms should be developed in order to gain control over sterical three dimensional orientations. Eric Drexler suggested that a universal assembler must be designed which would be able to build almost any desired nanostructure [56]. However it seems impossible at first glance unless the simple assembler are firstly built and these simple assembler build more complicated assemblers and so on to the point that we can have the universal assembler. An example of such assemblers is "Stewart platform" which comprises of twelve struts in an octahedral shape, six of them can have variable lengths [57]. Merkle has proposed



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an approach for shortening and lengthening of variable struts [55]. Positional assembly can be used to construct larger MBBs which subsequently self-assemble to the final desired nanostructures. Positional assembly consists of two strategies [21]: Additive synthesis in which MBBs are arranged to construct the desired nanostructure and subtractive synthesis in which small blocks are removed from a large building block or a primitive structure to form an eventual structure (like sculpture). Positional assembly approach has not been advanced because of so many limitations in designing suitable MBBs, robotic arms and technical problems. Instead of it, more attempts have been focused on self-assembly. Self-replication is another principal concept in nanotechnology. Self-replication is a process in which a product can mainly increase its own synthesis. In other words, it can catalyze the reaction(s) that would lead to its own production [58]. Some self-replication systems have been recognized and so many others are increasingly being developed. The main systems contain abiologic organic molecules, oligonucleotides and peptides, peptide nucleic acids (PNAs) [58]. In biotechnology and molecular biology self-replication is of great interest and some new approaches like "compartmentalized self-replication" (CSR) have been developed which is a technique for directing evolution of enzymes especially those which are involved in DNA replication [59]. The CSR is based upon the utilization of a polymerase enzyme which replicates exclusively its own encoding gene [59].

3.1. Self-assembly

Self-assembly is a process in which components spontaneously form ordered aggregates. Examples of such a phenomenon can be found from the molecular to macroscopic level [60]. Protein folding (Second, third or forth structure), DNA double helix, formation of lipid bilayers, colloids [61, 62] and crystals are some instances in which self- assembly is the dominant phenomenon. Self-assembly is largely influenced by the environment. The molecular aggregate which is formed by the self-assembly process, is an ordered array which is thermodynamically the most stable conformation for a macromolecule or number of macromolecules. Self-assembly occurs in liquid medium or near the interface to make it possible dynamic exchanges toward reaching the minimal energy level. Forces involved in structures formation are mainly weak non-covalent ones (hydrogen bond, electrostatic, van der waals, hydrophobic,…) but the number of interactions for formation of each region of molecular conformation are so high that can assure consistence and stability of the macromolecule and whole complex [60, 55] (like hydrogen bonds in second helical or beta-sheet structure of proteins). The main goal is directed self-assembly, and to design the desired nanostructures fashions of interactions between MBBs should be clearly understood. Fundamental principles can be founded for prediction of nanostructure's steric arrangement base upon their MMB composition by inspiration from relations which exist between first structure of proteins and later ones in a biomimetic way. Undoubtedly to achieve the knowledge to such rules information about intermolecular interactions and molecular simulations (for determination of interaction patterns between molecules) are of critical importance [6, 63, 64]. As it was mentioned before, self-assembly is a process which due to its dynamic nature demands a solution (fluid medium) or an interface as an environment [60] but there are some methods which mainly exploit solid surfaces for assembling of components. However, the assembled arrangements on the solid surface would subsequently self-assemble in the above appropriate environments. Such approaches would be discussed as "self-assembly using solid surfaces" in this context due to their significant importance while the typical methods like DCL would be described as "self-assembly in liquid medium". It is also possible to combine self-assembly methods with patterning ones such as nanoimprint lithography [65, 66], soft lithography and other methods [67].

3.1.1. Self- assembly Using Solid Surface



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Some important methods of this class involve DNA directed (self-)assembly on the solid surfaces, self-assembly at silicon surfaces, strain directed assembly, and lithography induced self- assembly (LISA) [68]. Strain directed assembly provides a way for fabrication and interconnection of wires and switches. In this approach a lithographically defined surface structure is integrated with a strain and compositionally controlled precipitation process. It is possible to introduce a functional group to the substrate which would couple with surface functionality [69]. This method can be used for semiconductor construction [67]. It is necessary to immobilize system components on a solid support in order to gain control over self-assembly process. There are various techniques for immobilization as described below.

3.1.1.1. Some Immobilization Techniques Immobilization of molecules on a solid support is useful for single molecule studies (like ligand-receptor interaction studies) and also for molecular manipulation. Molecules can be immobilized via covalent or non-covalent bonds. Covalent bonds mostly contain sulfide bonds between thiol-bearing molecules and a noble metal (like gold). Immobilization of alkane-thiol chains or proteins with cystine in their structures on a gold surface are two instances of covalent type [70]. In contrast, non- covalent bonds are more utilized in three kinds of immobilization [71]: 1- Affinity coupling via suitable antibodies.2- Affinity coupling by biotin-(strept)avidin systems and it's modification (Fig. 7.).3- Immobilized metal ion complexation (IMIC).

First method chiefly uses Streptococcal proteins A and G which show high affinity toward mammal immunoglobulins [71]. Second method i.e. biotin-streptavidin system is one of the most efficient approaches to construct semi-synthethic nucleic acid-protein conjugates [72]. Biotin-streptavidin affinity constant is about 1014 dm3mol-1 which is the strongest known ligand-receptor interaction [73]. This method provides the possibility for immobilization of most molecules. It is also possible to attach antibody fragments to the nucleic acid sequences or a nucleoprotein complex via such a technique (Fig. 8.).

A noteworthy targeting strategy has been proposed which uses biotin-streptavidin system [74]. In this method, pretargeting is done using streptavidin-antibody conjugate (antibody is specific for an individual cell marker for example a tumor marker). Then, targeting is done using biotinylated drug delivery system. It is possible to utilize biotinylated antibody in pretargeting stage and streptavidin conjugated with vector/ therapeutic agent for targeting. Specific antibody attaches to desirable cells and presence of biotin-streptavidin system would lead to attachment of drug vector to the antibody which is localized on the surface of target cells.

IMIC uses complexation between a metal which has been already immobilized on a support and macromolecules electron donor groups [71]. Table 1 shows some principal methods for immobilization of biomolecules to the surface [75]. Figure 9 shows some other immobilization methods which are mainly used for proteins. One of the paramount facts in the protein immobilization is inhibition of non-specific protein adsorption on the support. Some techniques have been also developed for such a purpose. Table 2 enumerates some of these techniques [75]. Crystalline bacterial cell surface layers (S-layer) can be exploited for immobilization using appropriate chemical and physical processes [76]. DNA oligomers can be used for site-selective immobilization of macromolecules. It is very noteworthy, because it becomes feasible to direct self-assembly process on a solid surface via DNA directed immobilization (DDI) [77]. Firstly, the desired site of the molecule is tagged by a DNA strand



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and then the complementary DNA strand is fixed on a solid surface. Thus, completely specific DNA hybridization is exploited to immobilize macromolecules with controlled steric orientation. This method has been successfully performed to immobilize gold nanoparticles [78]. Figure 10 depicts such a process.

3.1.1.2. DNA Directed (Self-)Assembly DNA can be used both for site- selective immobilization and as a linker and thus provides a scaffold for nanostructure assembling. Nucleic acid-protein conjugate synthesis and utilization of specific interactions between two complementary DNA strands, antigen- antibody and biotin- streptavidin can bring about powerful tools to direct the mode of nanostructure modules attachment. Last improvements in exerting genetic engineering techniques to the immobilized DNA sequences on a gold surface – like ligation, PCR, and restriction digestion – provides even more control over self- assembly process [79]. Figure 11 illustrates utilization of DNA- streptavidin conjugates in DNA directed assembly to construct nanostructures. Figure 12 represents usage of biotin-streptavidin system in DNA-directed self- assembly. Such a method can be applied to the inorganic nanocrystal molecules. DNA can be also employed for templated synthesis and it’s instance is silver nanowire construction using DNA backbone [81]. DNA has been also utilized to construct one, two or three dimensional frame-works [80]. Figure 13 depicts such structures.

It should be noted that DNA oligomer-tagged nanomodules can be attached together with favorite regioselectivity and in a controlled way. Detaching of assembled nanostructure from the solid support leads to nanostructure folding (depending on the environment conditions ) and formation of the eventual conformation.

3.1.1.3 Self-assembly on Silicon Surfaces Employing silicon surfaces for self-assembly is of more importance in the micro/nanoelectronic fields. Molecules and metals can be selectively deposited on a silicon template via such a method [82]. This resembles patterning techniques to some extent (silicon based microlithography). Some other substances have been proposed to be used in templated self-assembly like S-layer proteins [76], diatom frustules [83] and etc.

3.1.2. Self- assembly in Liquid Medium Instances of self-assembly in liquid phase consist of polymerizable amphiphiles [84], polymer and lipid utilization to form ordered aggregates like mono/bilayers, micelles and nanoparticles. Fluidic self-assembly using a template surface which is complementary to polyhedral components and employing liquid stream to select appropriate components is another approach [60]. Two other methods are: 1-Dynamic combinatorial libraries (DCLs) which has an outstanding position in the combinatorialchemistry.2- Designing molecular cages using host-guest chemistry.These methods are described below.

3.1.2.1 Dynamic Combinatorial Libraries (DCLs) A DCL comprises the number of components which interact together via the weak non-covalent bonds and reach to the equilibrium. In ordinary condition, there are so many possibilities for formation of ordered collections according to different probable composition of components. After adding a template or ligand, the dynamic nature of system allows it’s components to self-assemble in such a way



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that they can form the most thermodynamically stable aggregate in interaction with template. Through the numerous reversible bonds, equilibriation (after adding the template) proceed in a way that assembling of more stable receptor aggregates significantly increase. In contrast, concentration of thermodynamically unstable receptors (in relation with template) would be decreased. Main reversible reactions which exist in these systems involve metal-ligand coordination, hydrogen bond exchange, ester exchange, transamination, transimination , exchange of oximes, hydrazine and olefin metathesis and disulfide exchange [85]. Only disulfide exchange and olefin metathesis can operate under physiologic conditions [85]. The separation of the major aggregate formed after adding a template demands some appropriate analytical methods and it is one of the difficulties in designing some DCL systems. However, affinity chromatography or capillary electrophoresis coupled to the mass spectral analysis can be a solution for many cases [86]. Figure 14 presents an example of a DCL system before and after template addition. Figure 15 illustrates two common concepts in DCLs, namely casting and molding. These concepts are the basis of molecular recognition and receptor formation. The selection of best-fitted receptor to a given template is a feature of DCL which would lead to exploitation of an evolutionary approach to produce and separate the most appropriate receptors similar to something which happens in the natural evolution process. The attempts to direct evolution of high-affinity ligands for biomolecules in the new emerging field called "Dynamic Diversity" can have numerous applications in drug discovery [86]. DCLs are very promising for designing enzyme inhibitors and molecular containers and capsules [88].

3.1.2.2. Host – Gust Chemistry Approach Host - guest chemistry methods can be exploited to design superamolecules which are susceptible to recognition and specific binding to some special molecules. In these methods mostly, the inner surface of designed molecules (host or receptor) interacts with the gust or ligand surface and weak bonds between them determine the extent of specific binding and molecular recognition. After self-assembly, the component which forms host, adopts an individual conformation which often has a cavity or cleft for complete or relative entrapping of guest molecules. Although control over designing process and also recognition specificity in these methods are not as much as DCLs but in many cases, restrictions and designing difficulties are less than DCL systems. The major weak forces which are involved in formation of such receptors are hydrogen bonds and hydrophobic interactions. However other interactions like Br…Br, Cl…N, I...O, etc are used in smaller scale. Such receptors can be also synthesized on a solid support [89].

A vast number of molecules have been used for self-assembly, receptor formation and molecular recognition. Such molecular recognition contains some receptors for recognition of carboxylic acid groups (carboxylic acid recognition), peptide or carbohydrate recognition [90]. There are special methods and reactants for construction of each cyclic, container or linear structures. For instance a strategy for cyclic structures construction is utilization of triple and complementary hydrogen bonds between donor-donor-acceptor (DDA) group of one molecule and acceptor-acceptor-donor (AAD) group of a second molecule [91]. A common strategy for container complexes construction is using concave, bowl shaped building blocks like glycoluril, calixarenes (Fig. 16) or resorcinarenes. Introduction of groups which are capable of hydrogen bonding like urea and it’s derivatives make it possible to change the shape of capsule [91] (Fig. 17. and 18.).

As it was already mentioned, molecular capsules can be fabricated by dimerization of two concave subunits which are able to form hydrogen bonds in eventual structure, namely desired properties can be



13

introduced to achieve an ultimate structure by using appropriate concave subunits, linkers, or spacers like an example which has been depicted in Figures 19 and 20.

It is believed that after receptor formation at first, solvent molecules are entrapped inside it and then after guest addition, they replace solvent molecules. Adamatane and it’s derivatives are widely used for kinetic study of guest release and exchanges [89, 92, 93, 94]. Figure 21 shows such an exchange. Peptide nanotubes are made of chiral amino acids and can be used for drug delivery [95]. Besides, the adamantane constrained cyclic tripeptide, (Adm-cyst) 3 has been constructed which has a double-helical figure [96]. The L-cystine can give chirality to these nanotubes while utilization of achiral compounds like adamantane makes it possible to control the size, shape and conformation of these synthetic oligopeptides [96].

4. Discussion

4.1. Diamondoids for Drug Delivery and Drug Targeting Adamantane derivatives can be employed as carriers for drug delivery and targeting systems. Due to their high lipophilicity, attachment of such groups to drugs with low hydrophobicity would lead to increment of drug solubility in lipidic memberanes and thus uptake increases. Furthermore, incomparable geometric properties of adamantane and other diamondoids, make it possible to introduce several functional groups consisting of drug, targeting part, linker, etc to them without undesirable interactions. In fact, adamantane derivatives can act as a central core for such drug systems. Short peptidic sequences can be bound to admantane and provide a binding site for connection of macromolecular drugs (like proteins, nucleic acids, lipids, polysaccharides, …) as well as small molecules. Hence, short amino acid sequences can have linker roles which are capable of drug release in the target site. It is also noteworthy in self-assembly process. A successful instance is application of adamantyl moiety for brain delivery of drugs [97]. For this purpose, 1-adamantyl moiety was attached to several AZT (Azidothymidine) drugs via an ester spacer and these prodrugs could pass the BBB easily. The drugs concentration after using such lipophilized prodrugs was measured in brain tissue and showed an increase of 7-18 folds in comparison with AZT drugs without adamantane vector. Ester bond would be cleaved after passing BBB by brain tissue esterases. However, the ester link should be resistant to the plasma esterases. Inasmuch as the site of action for memantadine is central nervous system (CNS) and it has CNS affinity and further, Amantadine and Rimantadine can penetrate to CNS and cause some adverse effects, it has been proposed that adamantane might have an intimate CNS tropism [97]. Furthermore, because half-life of the two latter drugs in bloodstream is long (12–18 hours for Amantadine and 24-36 hours for Rimantadine in young adults), utilization of adamantane derivative carriers can prolong drug presence time in blood circulation. However, related data for each system should be obtained. Ultimately, it is of importance to note that adamantane has appeared as a successful brain-directed drug carrier. Adamantane has been also used for lipidic nucleic acid synthesis as a hydrophobic group [98].

As it was already mentioned, two major problems in gene delivery are nucleic acids low uptake by cells and instability in blood medium. Probably, an increase in lipophilicity using hydrophobic groups would lead to improvement of uptake and an increase in intracellular concentration of nucleic acids [98]. In this case, an amid linker was used to attach adamantane derivatives to a nucleic acid sequence [98]. Such a nucleic acids derivatization had no significant effect on hybridization with target RNA.



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Recently, synthesis of a polyamine adamantane derivative has been reported which has a special affinity for binding to DNA major grooves [99]. It should be reminded that most of polyamines have affinity for binding to RNA and thus making RNA stabilized and such a DNA selectivity is one of the outstanding features of said ligand. This positive nitrogen-bearing ligand has more tendency to establish hydrophobic interactions in deeper grooves due to its size and steric properties. Such an exclusive behavior occurs because ligand fits better to DNA major grooves. This bulky ligand size is the same as zinc-finger protein. The said protein binds to DNA major grooves (Fig. 22.).

Higher affinity of adamantane-bearing ligand to DNA, instead of RNA, arises from the presence of adamantane and leads to DNA stabilization. This fact can be exploited for using such ligands as stabilizing carrier in gene delivery. Admanatane causes lipophilicity increase as well as DNA stabilization. On the other hand, a targeting sequence can be utilized in order to achieve intracellular targeting.

Ligand/groove size-based targeting is also possible with less specificity by changing the bulk and conformation of ligand. It can be used, both, for targeting of special genum regions and for better understanding of an individual region folding in the genum. Such adamantane-bearing ligands ability to establish weak specific interactions with nucleic acids produces more control over self-assembly processes. Lipidic nucleic acids possessing adamantane derivative groups can be also exploited for gene delivery. Because the nanostructures which are made from pure DNA backbone (as shown in Fig. 13.) do not possess enough rigidity, introduction of adamantane cores to such structures can provide adequate solidity for maintaining the desired conformation.

Polymers conjugated with 1-adamantyl moieties as lipophilic pendent groups can be utilized to design nanoparticulate drug delivery systems. Polymer 1 in figure 23 which is synthesized by homopolymerization of ethyladamantyl malolactonate can be employed as highly hydrophobic blocks to construct polymeric drug carries [100]. In contrast, polymer 2 (Fig. 23.) which is synthesized by copolymerization of polymer 1 with benzyl malolactonate is water-soluble and it’s lateral carboxylic acid functions can be used to bind biologically active molecules in order to targeting as well. These polymers signify to produce pH dependant hydrogels and intelligent polymeric systems [100].

4.2. Diamodoids for Self –assembly 4.2.1. DNA Directed Assembly and DNA-Adamantane-Protein Nanostructures Due to the ability of adamantane for attachment to DNA, it seems that construction of well-defined constitutions consisting of DNA fragments as linkers between adamantane (and it’s derivatives) cores is theoretically possible and it can be a powerful tool to design nanostructured self-assemblies. The unique feature of DNA directed assembly, namely site selective immobilization, makes it possible to arrange completely defined structures. On the other hand, the possibility of introduction of vast number of substitutes, like peptidic sequences, nucleoproteins, hydrophobic hydrocarbon chains, etc to the adamantane core makes such a process capable of designing steric conformation via setting hydrophobic/ hydrophilic ( and other) interactions. In addition, due to the rigidity of diamondoid structures the required strength and integrity could be provided to such self-assemblies by this means.

Bifunctional admantane nucleuses, as a hydrophobic central core, can be used to construct peptidic scaffoldings (Fig. 24.) [101]. This fact indicates why adamantane is considered as one of the best MBBs. It seems an effective and practical strategy to substitute different amino acids on the adamantane core (Fig. 25.) and exploit nucleic acid sequences as linkers and DNA hybridization to



15

attach these modules. Thus, the DNA-Adamantane-Protein nanostructures can be obtained. The knowledge of proteins folding and conformations can be also helpful to inspire from biological systems how to design a desired conformation and to predict the ultimate conformation of said nanostructures according to a given composition of MBBs in a biomimetic way. Step by step assembly makes it possible to manage desired and accurate nanostructure formation and observation of the effect of each new MBB introduction. Such a controlled and directed assembly can be utilized to investigate molecular interactions, molecular modeling and study of relationships between the composition of MBBs and the final conformation of the nanostructures. Immobilization of molecules on a surface could facilitate such studies [71]. For adamantane cores nucleic acids attachment can be done in many ways. At least, two nucleic acid sequences as linkage groups are necessary for each adamantane core but structural development in desirable steric orientation can be achieved by changing the position of two said sequences with respect to each other on the adamantane core or introduction of more nucleic acid sequences.

Another noticeable point is that Glutamine dendrones 2 and 3 (Fig. 25.) dissolve slowly in warm water [101] which is an indication of the high flexibility of admantane for bearing different range of changesin physicochemical properties from a completely hydrophobic molecule to a hydrophilic one usingsubstitution of appropriate functional groups. In fact, over 20,000 derivatives of adamantane are knownand even more are possible [55,21]. The desired alterations can also be exerted on a nucleic acidsequence utilizing the new techniques developed in solid-phase genetic engineering for immobilizedDNA alteration. For instance, DNA ligation can be employed to join nanomodules (as well ashybridization) similar to which has been done on immobilized DNA in the case of gene assembly [79].As well as adamantane cores and DNA sequences, it possible to modify the amino acid parts of the saidnanostructures. For example, using some unnatural (synthetic) amino acids [102] with behaved foldingcharacteristics the ability of conformation fine-tuning would be improved. Moreover, polypeptides andnucleic acids are the major components for self-replication [58] and they might facilitate designing ofself-replication processes for the said nanostructures. Hence, assembling and composing of adamantanenucleuses as central cores, DNA sequences as linkers and amino acid substituents (on the adamantane)as conformation controllers would lead to design of DNA-Adamantane-Protein nanostructures withdesired and predictable properties.

4.2.2. Diamondoids for Host-Guest Chemistry The paramount aim in host-gust chemistry is to construct molecular receptors by self-assembly process so that such receptors could, to some extent, gain molecular recognition capability. Calixarenes, which are macrocyclic compounds, are one of the best building blocks to design molecular hosts in supramolecular chemistry. In 2002, the first synthesis of Calix[4]arenes which had been adamantylated on its upper rim was reported [103]. In these Calix[4]arenes, adamantane or it’s ester/carboxylic acid derivatives can be introduced as substituents (Fig. 26.). The purpose of this synthesis was to learn how to employ the flexible chemistry of adamantane in order to construct different kinds of molecular hosts. The X-ray structure analysis of p-(1-adamantyl) thiacalix[4]arene (compound (a) in Fig. 26) demonstrated that it contains four CHCl3 molecules, one of them was located inside the host molecule cavity, as shown in Fig. 27, and the host molecule assumed a cone-like conformation shapes ( Fig. 27.).

An important strategy to design host molecules is joining several concave monomers/units via a linker (see Fig. 19). These monomers /units are capable of hydrogen bonding. The synthesis of tetrameric 1,3-adamantane and it’s butyl derivative has been reported (Fig. 28) [104]. Introduction of some groups



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which are capable of hydrogen bonding (like urea , amines, hydroxyl groups, …) to the said tetrameric 1,3-adamantane derivative might probabely be exploited to construct host molecules. Calix[4]arenes are also utilized to design DCLs [105] and perhaps their adamantane derivatives can be employed in the same process for self-assembly and producing molecular receptors. Some other types of macrocycles have been synthesized using adamantane and its derivatives. Recently, a new class of cyclobisamides has been synthesized using adamantane derivatives which show the general profiles of amino acid (serine or cystine)-ether composites and they were shown to be efficient ion transporters (especially for Na+ ions) in the model membranes [106] (Fig. 29). Another interesting compounds which adamantane derivatives have been introduced to them in order to obtain cyclic frameworks are "crown ethers" (Fig. 30-a) [107]. The outstanding feature of these adamantane-bearing crown ethers (which are also called "Diamond Crowns") is that α-amino acids can be incorporated to the adamantano-crown backbone (Fig. 30-b) [107]. This family of compounds provides the valuable models for studying selective host-geust chemistry, ion transports and ion-complexation [107].

5. Conclusions

Diamandoids are organic compounds with unique structures and properties. They are one of the best candidates for molecular building blocks (MBBs) in molecular nanotechnology to design nanostructures with predetermined physicochemical properties. Some of their derivatives have been used as antiviral drugs for many years. Due to their flexible chemistry, they can be exploited to design drug delivery systems and also in molecular nanotechnology. In such systems, they can act as a central lipophilic core and different parts like targeting segments, linkers, spacers, or therapeutic agents can be attached to the said central nucleus. The Central core can be functionalized by peptidic and nucleic acid sequences and also numerous important biomolecules. Furthermore, some adamantane derivatives possess special affinity to bind to DNA and making it stabilized. It is an essential feature for a gene vector. Some polymers have been synthesized using adamantane derivatives which their application for drug delivery is under investigation. Adamantane can be used to constitute peptidic scaffolding and synthesis of artificial proteins. Introduction of aminoacid-functionalized adamantane to the DNA nanostructures would lead to construction of DNA-adamantane-protein nanostructures with desirable solidity and integrity. Diamondiods can be employed to construct molecular cages and containers and also for utilization in different methods of self-assembly. In fact, by development of self-assembly approaches and utilization of diamondoids in these processes, it would be possible to construct novel nanostructures especially to design effective and specific carriers for each drug.

List of abbreviations

5-HT 5-HydroxytryptamineAAD Acceptor-Acceptor-DonorAFM Atomic Force MicroscopeAMPA α-amino-3-hydroxy-5-Methylisoxazole-4-Propionic AcidAZT AzidothymidineBBB Blood-Brain BarrierBIO-STV Biotin-Straptavidin CNS Central Nervous System CSR Compartmentalized Self-Replication



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DCL Dynamic Combinatorial Library DDA Donor-Donor-Acceptor DDI DNA-Directed Immobilization F1 Fluorophore group FISH Fluorescent-In-Situ Hybridization Glu Glutamine HCV Hepatitis C Virus HIS Histidine IgG Immunoglobulin G IMIC Immobilized Metal Ion Complexation LDL Low Density Lipoprotein LISA Lithography Induced Self-Assembly NLS Nuclear Localization Signal NMDA N-Methyl-D-AspartatePCR Polymerase Chain ReactionPEG Poly Ethylene GlycolPEO Poly Ethylene OxidePNA Peptide Nucleic AcidPPV Poly PhenyleneVinyleneRME Receptor Mediated EndocytosisS-Layer Surface LayerSAM Self-Assembled MonolayerSTV StraptavidinTg Glass Transition TemperatureTNF-α Tumor Necrosis Factor-α

Acknowledgments The authors would thank Jennifer Anderson, Reza Bagherian and David Dziura for their help in bibliography and study of diamondoids synthesis and production.

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26

Table 1. Methods for immobilization of active biomolecules to the surface. (From [75])

Methods Comment Non-specific adsorption Little control is afforded of protein

orientation or activity; low durability

Non-specific covalent immobilization Little control is afforded of protein orientation or activity

Immobilization on an antibody surface Using monoclonal antibodies, protein orientation can be controlled

HIS tags Histidine sequences (HIS tags) can be specifically engineered into proteins

for attachment and orientation

Biotin/straptavidin A flexible strategy for tightly fixing protein to surfaces; in vivo biological reaction to straptavidin is a concern

Crystallized protein layers Useful only in limited cases

Immobilization to a template structure An evolving field

Biomimetic recognition sites An evolving field

Incorporation in a supported bilayer As an emulation of the cell membrane this

has the possibility to stabilize fragile proteins

Nucleotide conjugation/hybridization Many possibilities are being explored Electrostatic A non-specific approach to immobilizing

proteins when the protein has an isoelectric point higher or lower than seven and a surface has a positive or negative charge



27

Table 2. Strategies to achieve protein-resistant (non-fouling) surfaces. (From [75])

Surface strategy Comment PEG Effective but dependent on chain density at the

surface; damaged by oxidants

PEG-like surface by plasma Applicable for the treatment of many substrates and deposition geometries; highly effective

PEG oligomers in self-assembled Highly active; applicable for precision molecularly monolayers engineered surfaces; durability to elevated

temperatures is low

PEG-containing surfactants adsorbed A simple method for achieving non-foudingTo the surface surfaces; durability may be low and high surface

Densities are hand to reach

PEG blocks in other polymers coated May provide a relatively low density of surface on the surface PEG groups

Saccharides Nature’s route to non-fouling surfaces; some successes but much territories remains to explored

Choline headgroups (phosphatidyl Has shown good success in many applications Choline )

Hydrogen bond acceptors Possibly, this principle imparts non-fouling properties to PEG surfaces; this is leading to new discoveries of surface functional groups for non-

fouling

Adsorbed protein layer A pre-adsorbed protein layer resists further adsorption of proteins; this approach, long

used by biologists, is easy to implement but of low durability

Hydrogels, in general PEG is in this class; many other hydrogels have shown non-fouling behavior



Figure 1.

Chemical structures of diamondoids. They can be superimposed upon diamond lattice. Different views from higher diamondoids reflect their fascinating structures. Please note that the number of possible

attachments for cyclohexane rings would significantly increase with increment of "n" value in diamondoids common formula. In other words the number of isomers thus increases.



Figure 2.

-Left: The quasi-cubic units of crystalline network for 1,3,5,7- tetrahydroxyadamantane is similar toCsCl. Molecules have been shown as spheres and hydrogen bonds as solid linking lines. –Right:

The same crystalline structures have been shown in more details (From [7]).



Figure 3.

(a) Amantadine. (b) Rimantadine.

Figure 4.

(Left) 1,3-dichloro-5-(1-admantyl) benzene monomer and (Right) adamantly-substituted poly(m-phenylene) (From [27] ).



Figure 5.

Schematic drawing which shows adamantane as a molecular probe with three fluorophore groups (F1) and a targeting part (TG) for specific recognition (From [32]).

Figure 6.

Key events in intracellular targeting. The drug-containing nanoparticles should be recognized via a targeting part ( ) which interacts specifically with some domains of a receptor in the receptor

targeting process. Uptaking of nanoparticles is done through receptor-mediated endocytosis (RME) and endosomes are formed. Endosomes should be disrupted by membrane-lytic agents and release their

contents in the cytoplasm. The other possible route is integration of endosomes to the lysosome which is not desired for acid-sensitive drugs. The third destination is nucleus which demands specific

intracellular targeting oligopeptides.



Figure 7.

Biotin-straptavidin (Bio-STV) systems are effective tools for coupling of different types of molecules. In the first step a biotinylated functional macromolecule (FM) is coupled to the DNA-STV conjugate.

In the second step three biotinylated modulators attach to the residual valances of STV. These low molecular weight modulators can give a special folding to the macromolecule or complete it's

functionality.

Figure 8.

Application of Bio-STV systems in order to link an antibody (as a protein) to a DNA-marker (as a nucleic acid sequence) in the immuno-PCR method. DNA has been bis-biotinylated for this purpose.

(From [72] )



Figure 9.

Some methods for immobilization of proteins (from [108]). There are also some immobilization methods for proteins. Special interests are focused on these matters because they can find numerous applications in fabrication of nanodevices. Some of them are enumerated here [108]: (a) Physical adsorption; this approach is not very complicated and uses surface of carbon electrodes,metal oxides or silica oxides. The adsorbed proteins on the surface constitute a self-assemblemonolayer (SAM) with random orientations. Although modification of proteins and surface canimprove the ability of orientation controlling, but proteins are in the risk of denaturation and multiplelayers which are probably formed make the accessibility of immobilized molecules difficult to thesubstrates (Fig. a.).(b) Inclusion in polyelectrolytes or conducting polymers; In this case a non-oriented multi layer filmwould be formed. Polyelectrolytes or conducting polymers provide a matrix in which the proteins aretrapped and attached to the surface or adsorbed (Fig. b.).(c) Inclusion in SAM; Using thiolated hydrocarbon chains it is possible to produce a membrane-likemonolayer on a noble metal through which proteins can be located with non-specific orientation (lefthand part). Utilization of chains with different lengths would result in a SAM with definite topography(depressions and holes) that can give a specific orientation to the proteins (right hand) (Fig. c.).(d) Non-oriented attachment to SAM; In this approach the chains which form self-assemblemonolayer (SAM) possess a functional group at their ends and react non-specifically with differentparts of a protein. So, the orientation is random (Fig. d.).(e) oriented attachment to SAM; The principles is like the previous approach but the functional grouphere interacts specifically just with one domain or part of a given protein and hence a definiteorientation is obtained. The structure of proteins cab be chemically or genetically modified for thispurpose (Fig. e.).(f) Direct site-specific attachment to gold; It is done by attachment of a unique cystine of an outerdomain to the gold. In this field also genetic engineering would be very useful. The orientation iscompletely controlled (Fig. f.).



Figure 10.

DNA microarrays can be exploited to immobilize oligonucleotide-modified gold nanoparticles site-selectively. Two capture oligonucleotides, cA and cB, have been already attached to a solid glass support to make DNA microarrays. On the other side, the gold nanoparticles have been tagged by several oligonucleotides, A, which are exclusively complementary to the capture oligonucleotide cA. (A) The fluorescent probe, Cy5-cA, which contains the capture oligonucleotide cA, was utilized toprove the fact that there is not any unspecific hybridization in the absence of oligonucleotide A-containing gold nanoparticles (negative control). Lack of signals confirms this expectation. (B)Fluorescent pattern obtained after addition of gold nanoparticles. The Cy5-cA fluorescent probe detectsthe successful DDI of gold nanoparticles. (C) Positive control was obtained using a differentfluorescent probe, Cy5-B, containing oligonucleotide B which is complementary to the captureoligonucleotide, cB. Please note that the arrangement of spots is totally different in regard to theprevious image (Original diameter of spots = 200µ) (From [78]).



Figure 11.

Schematic representation of DNA directed assembly. Employing Bio-STV systems makes it available to attach a variable and extensive range of macromolecules to the DNA tags in order to DDI and after that DNA directed assembly. A 5'-thiolated oligonucleotide (like given sequences of a-f) is coupled with a straptavidin molecule to form conjugate 1. This can be used either as an auxiliary toll in DDI of different biotinylated macromolecules 2 or to fabricate and assemble nanoaggregates 3. In 2 one valence of tetravalent straptavidin has bee occupied by a biotinylated antibody and the second valence by a thiolated DNA tag in order to immobilize antibodies. The DNA microarray containing complementary sequences (a'-f ' ) was used as a solid support for DDI and further assembly of tagged nanomodules to form nanoaggregate 3. This method was first used for site-selective immobilization of proteins and later to assemble nanocrystall molecules from gold nanoclusters. Biometallic nanostructure 4 was obtained from conjugation of gold nanoparticles and conjugate 1. Nanostructure 5 comprises nanostructure 4 and aggregate 1-containing biotinylated immunoglubolins. The 3' end of oligonucleotides have been shown by arrowheads, biotin is represented as labled quadrants of STV (from [80]).



Figure 12.

Oligomeric DNA-STV conjugates 6 self-assembles from 5',5'-bisbiotinylated DNA sequences and straptavidin (STV) as a linker. Thermal treating of DNA-STV conjugate 6 would lead to formation of

nanocycles 7 which their AFM image has been shown at the bottom (from [80]).



Figure 13.

The "sticky ended" DNA strands associations are used to construct DNA-made nanostructures like "truncated octahedron" (left) and a DNA molecule with the connectivity of a cube (right). The rigidity of the molecules can be improved to some extant by using DNA crossover molecules (From [109]).



Figure 14.

An example of a DCL which consists of hydrazone-based pseudopeptide macrocycles. The HPLC chromatogram indicates that there are so many compositions possible before addition of template, namely Li+, (upper trace) but after addition of Li+ template the most thermodynamically stable composition becomes predominant (lower trace) (From [87]).



Figure 15.

Illustration of the "casting" and "molding" concepts in DCLs. In "casting" the components come together and constitute a cavity in which the guest molecules can be entrapped. In "molding" the components collect around a ligand and form the best aggregates complementary to the ligand shape. (From [87])



Figure 16.

A) The chemical structure of calix[4]arenas. B) Calix[4]arene hetrodimers can produce molecularreceptors with different shapes. (From [110])



Figure 17.

Introduction of hydrogen bonding groups to the calix[4]arenes to design appropriate shapes with enough stability. a) Dimeric capsule of urea substituted calyx [4] arenes. b) Hydrogen bonding can provide essential interactions to keep bulky groups closely together and coalescence of units to form a cylindrical cavity inside the dimeric capsule. (Reproduced from [91])



Figure 18.

Urea substituted calix[4]arene capsule. (From [110])



Figure 19.

Utilization of concave units for self-assembly of molecular receptors. a) Each unit comprises of two subunits and a spacer which attaches them to each other. b) Dimeric receptor as a result of hydrogen

bonding between units. (From [90])



Figure 20. Shows the concave shape of each monomer presented in Figure 19 from the side view. Two monomers interact together to form a molecular container via hydrogen bonds. From top view the orientation of

these two monomers seems like a cross.



Figure 21.

Two solvent molecules can be replaced by 1-adamantanecarboxylic acid. (From [90])

Figure 22.

(a) One of the adamantane derivatives which can react with appropriate amines to form polyamines.Both adamantane ligand (c) and zinc-finger protein helix (b) have the similar thickness and size (viewfrom the top). (From [99])



Figure 23.

Polymer (1): poly (ethyladamantyl B-malate) and polymer (2): poly(B-malic acid-co-ethyladamantyl B-malate) (From [100] ).



Figure 24.

Adamantane nucleus with amino acid substituents creates a peptidic matrix. The represented structure is Glu4-Glu2-Glu-[ADM]-Glu-Glu2-Glu4 (From [101]).



Figure 25.

Amino acid substituted adamantane cores can be employed as diverse nanomodules. (The figure has been reproduced from [101]).



Figure 26.

a) Synthesis route of the molecule (b): (i) S8, NaOH, tetraethylene glycol dimethyl ether, heat, (28%)b) Adamantane Upper rim derivative based on the thiacalix[4]arene platform.c,d) The carboxylic acid and ester derivative of adamantane can be also used as substituents. (From

[103]).



Figure 27.

Lateral stereo views of adamantane-derivative thiacalix[4]arene (top) presented in Figure 26. A CHCl3 molecule has been entrapped inside the inclusion compound. The bottom view (left bottom) and top view (right bottom) have been also shown. H atoms have been removed from the inclusion compound for more clarity. (Cl, OH, S, H and C atoms have been colored green, red, yellow, white and gray respectively).



Figure 28.

Synthesis of adamantane tetramers. Reagents and conditions: (a) Br2, CCl4, 30°C, 72 h; (b) Na, n-octane, reflux, 12 h (From [104] ).

Figure 29.

The serine-based cyclobisamides containing adamantane derivatives show an efficient ion transport activity in model membranes (From [106]).



Figure 30.

a) The crown ethers containing adamantane nucleus(es) in their macrocyclic frameworks.b) Amino acid-incorporated "diamond crowns" are useful models for the molecular studies in the host-guest chemistry and in the other fields (From [107]).



diamondoids as molecular building blocks for ......(2). university of illinois at chicago (m/c 063),...

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