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 an increment of drug solubility in lipidic membranes and thus their uptake will increase. Furthermore, favorable geometric properties of adamantane and other diamondoids make it possible to introduce to them several functional groups, consisting of drug, targeting part, linker, and the like, without undesirable interactions between such groups. In fact, adamantane derivatives can act as a central core for such drug systems. Short peptidic sequences bound to adamantane will provide binding sites for connection of macromolecular drugs (such as proteins, nucleic acids, lipids, polysaccharides, etc.) as well as small molecules. Hence, short amino acid sequences can have linker roles, which are capable of drug release in the target site.

There are some successful instances of adamantyl moiety application for brain delivery of drugs [51]. For this purpose, 1-adamantyl moiety was attached to several AZT (Azidothymidine) drugs via an ester spacer and these prodrugs could pass the blood-brain barrier (BBB) easily. The drug concentration after using such a lipophilized prodrug was measured in the brain tissue and showed an increase of 7-18 folds in comparison with the same AZT drug without the adamantane vector. The 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 Memantine is the central nervous system (CNS) and it has CNS affinity and further, Amantadine and Rimantadine can penetrate to the CNS and cause some adverse effects, it has been proposed that adaman-tane might have an intimate CNS tropism [51]. Furthermore, because half-life of the two latter drugs in the bloodstream is long (12-18 hours for Amantadine and 24-36 hours for Rimantadine in young adults), utilization of adamantane derivative carriers can probably 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-directing drug carrier.

Another example of adamantane utilization for brain delivery of poorly absorbed drugs is the conjugation of a Leu-enkephalin analogue, [D-Ala2] Leu-enkephalin, with a 1-adamantane moiety [52]. The antinociceptive effect of Leu-enkephalin disappears when it is administered peripherally because it would be decomposed by proteolytic enzymes and cannot penetrate into the CNS. It is feasible to conjugate the [D-Ala2] Leu-enkephalin with a 1-adamantane vector via an ester, amide, or a carbamate linkage in order to enhance the drug lipophilicity and thus facilitate its delivery across the blood-brain barrier [52]. The adamantane-conjugated [D-Ala2]

R Figure 3.9. The adamantane-conjugated

[D-Ala2] Leu-enkephalin prodrugs [52].

(!) R = NH2-Tyr-(D-Ala)-Gly-Phe-Leu-C0-0-(II) R = NHrTyr-(D-Ata)-Ciy-Phe-Leu-CO-NH

(!) R = NH2-Tyr-(D-Ala)-Gly-Phe-Leu-C0-0-(II) R = NHrTyr-(D-Ata)-Ciy-Phe-Leu-CO-NH

Leu-enkephalin prodrugs (Figure 3.9) are highly lipophilic and show a significant antinociceptive effect because of their ability to cross the BBB [52]. These results suggest that the adamantane moiety is a promising brain-directing drug vector providing a high lipophilicity, low toxicity, and high BBB permeability for sensitive and poorly absorbed drugs [52,53].

Adamantane has been also used for lipidic nucleic acid synthesis as a hydrophobic group [54]. Two major problems in gene delivery are nucleic acids low uptake by cells and instability in the 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 [54]. In this case, an amide linker is used to attach the adamantane derivatives to a nucleic acid sequence [54]. Such a nucleic acid derivatization has no significant effect on hybridization with RNA as the target. Lipidic nucleic acids possessing adamantane derivative groups may be also exploited for gene delivery.

Recently, synthesis of a polyamine adamantane derivative has been reported which has a special affinity for binding to DNA major grooves [55]. Such DNA selectivity of this ligand is one of its outstanding features. It should be pointed out that most of the polyamines have an affinity for binding to RNA and thus making RNA stabilized. This positive-nitrogen-bearing ligand has more of a tendency to establish hydrophobic interaction with deeper DNA grooves due to its size and steric properties. Such an exclusive behavior occurs because this ligand fits better into the DNA major grooves. This bulky ligand size works the same as the zinc-finger protein, which also binds to DNA major grooves.

Higher affinity of adamantane-bearing ligands to DNA, instead of RNA, probably arises from the presence of adamantane and leads to DNA stabilization. Adamantane is actually the reason for lipophilicity increase as well as DNA stabilization of such ligands. This property may be exploited for using such ligands as stabilizing carriers in gene delivery. Furthermore, the ligand/groove size-based targeting may also be possible with less specificity by changing the bulk and conformation of the ligand.

Polymers conjugated with 1-adamantyl moieties as lipophilic pendent groups can be utilized to design nanoparticulate drug delivery systems. Polymer #1 (Figure 3.10), which is synthesized by homopolymerization of ethyladamantyl malolactonate, can be employed as a highly hydrophobic block to construct h2 h o—c—c —c h2 h o—c—c —c a h2 h2 ,c—o—c —c a o

Polymer (1)

COOH

COOH

Polymer (2)

Figure 3.10. Polymer (1): poly (ethyladamantyl p-malate) and polymer (2): poly(|3-malic acid-co-ethyladamantyl p-malate) [56].

polymeric drug carriers [56]. In contrast, polymer #2 (Figure 3.10), which is synthesized by copolymerization of polymer #1 with benzyl malolactonate, is water soluble. Its lateral carboxylic acid functions can be used to bind biologically active molecules in order to achieve targeting as well. These polymers may be also used to produce pH-dependant hydrogels and intelligent polymeric systems [56].

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