The eukaryotic cell cycle (adapted from [54]). 

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... is angiotensin-converting enzyme inhibitors (ACEI). Not only they are used to treat hypertension, but they can also be used to treat congestive heart failure, myocardial infarctions and diabetic nephropathy. Temocapril (2-[(2 S )-6-[[(2 S )-1-ethoxy- 1-oxo-4-phenylbutan-2-yl]amino]-5-oxo-2-thiophen-2-yl-1,4-thiazepan-4-yl]acetic acid, Figure 7), an ACEI prodrug, can convert more quickly into its diacids after administration then other ACEI prodrugs [33]. Since temocapril has shown great success with animal studies, human studies were conducted with patients suffering from hypertension and found it to be effective in lowering blood pressure and temocapril is currently available to the public in Japan [34]. It is thought that the success of temocapril can be attributed to its unique ability to act as a scavenger for oxygen free radicals [35]. Recently, a study by Kim et al. reported that the combination of temocapril with olmesartan medoxomil ( CS-866, 5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(2H-tetrazol-5- yl)phenyl]phenylmethyl]imidazole-4-carboxylate), an angiotensin II AT 1 receptor inhibitor prodrug, prevented intimal thickening after balloon angioplasty [35]. In vivo , olmesartan medoxomil can also quickly covert to an active acid metabolite RNH-6720 by de-esterification [36]. The conversion process generally occurs in the gut and is not dependent on cytochrome P 450 . The enhanced suppression of vascular smooth muscle cell proliferation is speculated to be mediated with either activated PDGF- β receptor or bradykinin or NO [35]. Current treatments for pulmonary hypertension, i.e. when the lungs experience an increase in blood pressure, involve vasodilators and anticoagulants drugs that can inhibit cell proliferation and platelet aggregation [37]. Progressive pulmonary hypertension is defined as the buildup of collagen in pulmonary arteries which end up promoting fibroproliferation. Available drugs such as β -amino- propionitrile (C 3 H 6 N 2 ) and D -penicillamine ((2 S )-2-amino-3-methyl-3-sulfanylbutanoic acid) can inhibit collagen proliferation, but are toxic with long term use and also can inadvertently inhibit elastogenesis [38]. Proline analogue drugs are restricted due to high excretion rates and toxic side effects [38]. cis -4-Hydroxy- L -proline is linked via a lysine residue to poly(ethylene glycol) (CHOP- PEG) in order to lower its toxicity and promote its retention in blood vessels undergoing fibrosis. CHOP-PEG is a prodrug that inhibits fibrosis by suppressing the transforming growth factor- β /Smad signaling pathway [38]. In a study using a rat model with pulmonary hypertension induced by hypoxia, the CHOP-PEG had a 2x10 2 fold rate of fibrosis inhibition than monomeric CHOP while allowing the drug to be released in a dose dependant manner. [39] These preliminary data warrants further investigation of CHOP-PEG as a potential therapeutic agent for pulmonary hypertension and other diseases linked to fibroproliferation. Atherosclerosis is a term used to describe an artery that has been hardened due to multiple formation of plaque that is generated by plasma proteins such as lipoproteins which are responsible to transport cholesterol and triglycerides. It has been shown by clinical and animal studies that estrogen can inhibit the occurrence of coronary atherosclerosis by blocking angiotensin-converting enzymes [40, 41]. Also an added benefit of estrogen is that it elevates the production of endothelium-derived NO which reduces vascular smooth muscle cell (VSMC) proliferation and leukocyte adhesions [42, 43]. Estrogen replacement therapies for postmenopausal women were contested because of discouraging clinical studies that showed poor cardiovascular protection and increase risk of breast cancer [44]. 17- -Estradiol (8 R ,9 S ,13 S ,14 S ,17 S )-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]- phenanthrene-3,17-diol, Figure 8), which is the most common estrogen hormone found in humans, has been linked to stop the initiation and the development of atherosclerosis in animal models [45]. Once inside the body, 17- β -estradiol is metabolized to 2-methoxyestradiol (2-ME) through methylation. 2- Methoxyestradiol can block rat and human VSMC migration and proliferation in spite of the mediator that is involved in controlling these processes with no affinity towards estrogen receptors [46]. The first in vivo evidence that 2-methoxyestradiol can guard against atherosclerosis was presented by Barchiesi et al. [47], who not only demonstrated the efficacy of 2-methoxyestradiol, but also provided an explanation for the involvement of 2-methoxyestradiol in the intracellular signaling pathway. The authors proposed that 2-methoxyestradiol inhibits cell division by blocking the expression and activation of cyclin and cyclin-dependent kinases (Cyclin-D1/cdk4), the expression of cdk inhibitor p27, tubulin polymerization and the expression of cyclooxygenase-2 (Figure 9). While Barchiesi et al. provided a detailed understanding of the processes involved in reducing vascular hardening, there is still no satisfactory explanation on what triggers 2-methoxyestradiol to initiate these processes. Overall, the work by Barchiesi and co-workers has provided solid expectation that 2-methoxyestradiol could be a suitable drug for the treatment of cardiovascular diseases for women without increasing the risk of breast cancer and also has the potential for therapeutic use in men too. Most recently, 2-hydroxyestradiol (2OHE) was discovered as a prodrug of 2-methoxyestradiol with poor affinity towards estrogen receptors [48]. The 2-hydroxyestradiol conversion process is catalyzed by catechol- O -methyltransferase (COMT), which is an enzyme present in high levels in erythrocytes [49]. Generally, 2-hydroxyestradiol inhibits proliferation of smooth muscle cells (SMCs) in cells, but in studies where COMT was removed, the inhibition did not occur [50]. This further proves that COMT does mediate the conversion of 2-hydroxyestradiol to 2-methoxyestradiol. Apart from blocking SMCs growth, 2-hydroxyestradiol has been found to guard against puromycin aminonucleoside- induced nephropathy [51], monocrotaline-induced pulmonary hypertension [52] and angiotensin II- induced renal and cardiovascular injury [53]. In vivo studies with male rats demonstrated that the conversion of 2-hydroxyestradiol to 2-methoxyestradiol is very efficient and rapid, suggesting that the administration of 2-hydroxyestradiol is bioequivalent to the administration of 2-methoxyestradiol [48]. From a pharmacological therapeutic perspective, having 2-hydroxyestradiol bioequivalent to 2-methoxyestradiol is advantageous because 2-hydroxyestradiol is chemically less stable and is easily formulated into a drug, as opposed to 2-methoxyestradiol. Zacharia et al. [48] have found that the methylation of 2-hydroxyestradiol occurs at a greater rate in coronary than in aortic VSMCs and endothelial cells (ECs). In aortic VSMCs, the formation of 2-methoxyestradiol is blocked by catecholamines, which are found in higher amounts in aortic cells then coronary cells. Also COMT is not only responsible for mediating the production of 2-methoxyestradiol, but also for the breakdown of catecholamine. A potential alternative approach for improving estradiol delivery was presented by Zovko et al. [55] where they bound poly( α , β -( N -2-hydroxyethyl- DL -aspartamide))-poly( α , β -( N -2-aminoethyl- DL aspartamide)) copolymer (PAHA) to estradiol-3-benzoate (EB). By conjugating the drug to the polymer, they expected to increase the estradiol solubility, prolong its release and increase stability. To date, there has not been any report that demonstrates the clinical efficacy of PAHA-EB. Recent findings by Tanguay and co-workers [56] presented a debatable notion on whether direct local delivery of a drug at the injured site is more efficient than the produg approach for combating restenosis following PTCA. In their study, a single dose of 17- β -estradiol was administered locally at the time of stent implantation with porcine models suffering from coronary arterial injury. After introduction of 17- β -estradiol, all pigs experienced a reduction in SMCs growth compared to the control model, lower amount of inflammation and improved vascular reendothelialization after 28 days post-stenting procedure [56]. These results demonstrate the potential of direct local delivery of 17- β -estradiol in treating and preventing neointimal hyperplasia and late stent thrombosis. It is vital to design drug delivery systems where the carrier can actively release its drug specifically inside the diseased tissue. Andresen et al. [57] introduced secretory phospholipase A 2 as a site-specific trigger to prodrug loaded liposomes for the treatment of cancerous tissue. Another interesting development by Brioschi et al. [58] describe the application of solid lipid nanoparticles as effective drug vehicles for treating brain tumors. Recently, human mesenchymal stem cells from adipose tissue were introduced as delivery vehicles for site-specific enzyme prodrug conversion approach for chemotherapy [59]. Although these different prodrug delivery strategies described above allowed better control of drug distribution, metabolism, and elimination, they serve only for the treatment of cancer type diseases. There is a small amount of literature that reports new delivery strategies that provides specific and controlled release of prodrugs for the treatment of cardiovascular diseases as described below. A method that unites the prodrug approach with targeting specificity, where the drug is inactive during transport and then active when released to specific tissue targets without any toxic affects would be very effective in the field of drug delivery. Based on this theory a two-step approach called ADEPT (the antibody-directed enzyme prodrug therapy) was developed and showed good ...