1. Introduction
In the time of transition from premenopausal state to postmenopausal state the capacity of ovary producing sex hormones including estrogens, progesterone and testosterone cuts down [1]. Due to the menopause the level of serum oestrogen dramatically decreases, which increases the production of bone-resorbing cytokines and osteoblasts and then increases the number and activity of osteoclast, thereby increasing the bone loss [2]. Hormonal replacement therapy (HRT) is able to prevent bone loss for sex hormones-deficient menopausal women and consequently is of clinical importance for the treatment of osteoporosis. [1-3] In Europe and USA the osteoporosis prevention of 25-50% of the post-menopausal women rely on HRT [2,5,6]. In past years, however, the large international studies, such as the randomized Woman Health Initiative, the observational Million Women Study and the Women’s International Study of long Duration, discussed both of the adverse and beneficial effects of post-menpausal HRT [7]. In respect of the adverse effects, the discussion was focused on HRT induced risk of breast cancer [8-11], venous thromboembolism [12], stroke and myocardial infarction [13], as well as coronary heart diseases [14]. To limit these adverse effects a series of regimens of HRT, such as continuous combination of oestrogen and progestogen or continuous oestrogen and interruptted progestogen [15], and with dehydroepiandrosterone as a new strategic tool [16], were developed. In general these regimens confer no positive result, and thus new strategies are still needed.
Osteoporosis relates to both the decrease of the formation of osteoblast-modulated bone and the increase of the resorption osteoclast-modulated bone. Estrogen directly up-modulates the activity and the proliferation of osteoblasts, and/or regulats the gene expression in osteoblasts and osteoclasts [17-20]. Bone resorption is regulated by the adhesion of osteoclasts to the surface of the bone, which is mediated by the receptor αvβ3 integrin and its recognition to RGD (Arg-Gly-Asp) containing protein of osteoclasts [21]. These suggest that the activity and proliferation of osteoblasts and the adhesiveness of osteoclasts can be simultaneously up-regulated with estrogen and down-regulated with RGD peptide, respectively. On the other hand, it was explored that the covalent modifications of hydrocortisone and estrone with kyotorphin (a dipeptide, Tyr-Arg) may increase the analgesic activities of hydrocortisone and estrone [22], as well as the covalent modifications of hydrocortisone and prednisolone with urotoxins (Gly-Asp-Gly, His-Gly-Gly, His-Gly-Lys and His-Gly-Lys-NHNH2) may increase the immunosuppressive activities of hydrocortisone and prednisolone [23]. Similarly, the anti-osteoporosis activities of estrone and estradiol were enhanced by growth hormone releasing peptides (GHRPs: Tyr-Gly-Gly-Phe-Met-NH2, Tyr-Gly-Gly-Phe-Met, Tyr-Gly-Gly-Phe-Leu-NH2, Tyr-Gly-Gly-Phe-Leu, Tyr-Gly-Gly-Phe-Gly-NH2 and Tyr-Gly-Gly-Phe-Gly) [24-26]. In this context a strategy to enhance anti-osteoporosis potency and reduce adverse effects of HRT was practiced by covalent modifications of sex hormone with RGD-peptides.
2. Covalent modifications of estrogen with RGD-peptides and ip treated ovariectomy mice
Estrogens including estrone, estradiol, estriol, conjugated estrogen and tibolone have been widely used in HRT. Upon the promotion of the enzyme both estrone and estradiol can be converted to ertriol. Conjugated estrogen is an oral estrogen isolated from the urine of gravid horse and contains estrone monosodium sulfate (50.0% - 63.0%), equilin monosodium sulfate (22.5% - 32.5%), a few of 17α-estradiol monosodium sulfate and equilenin monosodium sulfate. Tibolone is an analog of norethynodrel. Of these estrogens, estrone and estradiol are the common parents and estradiol is the major agents of HRT. Thus estradiol and estrone were covalently modified by RGD-peptides (
2.1. Covalent modification of estradiol with RGD-tetrapeptides decreasing bone turnover
Using succinyl group as the linker the covalent modifications of the 17β-hydroxy of estradiol with RGD-tetrapeptides provided conjugates
2.2. Covalent modification of estradiol with RGD-tetrapeptides inhibiting bone loss
The effects of ip injection of
2.3. Covalent modification of estrone with RGD-tetrapeptides inhibiting bone turnover
Using carbonylmethyl group as the linker the covalent modifications of the 3-hydroxy of estrone with RGD-tetrapeptides provided conjugates
2.4. Covalent modification of estrone with RGD-tetrapeptides preventing bone loss
The effect of ip injection of
2.5. Covalent modification of estrogen with RGD-tetrapeptides inducing no endometrial cell hyperplasia
The effects of ip injection of
2.6. Summary of covalent modification of estrogen with RGD-tetrapeptides
With RGD-tetrapeptides modifying one hydroxyl group of estradiol and estrone resulted in 9 conjugates. On ovariotomy mouse model and at 110.3 μmol/kg of ip dose their anti-osteoporosis activities were significantly higher than that of estradiol and estrone themselves. In contrast to estradiol and estrone themselves, the anti-osteoporosis therapy of these conjugates induced no endometrial cell hyperplasia. It is commonly accepted that osteoporosis relates to both the decrease in bone formation modulated by osteoblasts and the increase in bone resorption modulated by osteoclasts. In HRT, estradiol and estrone are used to treat the decrease in skeletal muscle and bone by the direct modulation of osteoblastic activity and proliferation or by the regulation of gene expression in osteoblasts and osteoclasts. Bone resorption is regulated by the binding of osteoclasts to the bone surface and, therefore, depends upon osteoclast adhesiveness. This bone adhesion process is mediated by RGD-tetrapeptides binding integrin receptor on cell surface. This action of RGD-tetrapeptides should be responsible for both the increased anti-osteoporosis activity and the decreased endometrial cell hyperplasia of the conjugates. Due to ovariotomy mouse model simulates the bone loss condition of postmenopausal women these RGD-tetrapeptides modified estradiol and estrone should be promising candidates for HRT use.
3. Covalent modification of estrogen with RGD-octapeptides and orally treated ovariectomy mice
It was explored that the modification of RGD-tetrapeptides with oligopeptides usually increased their bioactivities [28, 29], suggesting the modification of RGD-tetrapeptides with RGD-tetrapeptides may result in increase of the activity of down-regulating proliferation of osteoblasts and the adhesiveness of osteoclasts. In this context estradiol and estrone were modified with RGD-octapeptides (
3.1. Covalent modification of estradiol with RGD-octapeptides inhibiting bone turnover
Using succinyl group as the linker the 17β-hydroxy of estradiol was modified with RGD-octapeptides and provided
3.2. Covalent modification of estradiol with RGD-octapeptides preventing bone loss
The effect of orally administration of
3.3. Covalent modification of estrone with RGD-octapeptides inhibiting bone turnover
Using carbonylmethyl group as the linker the 3-hydroxy of estrone was modified with RGD-octapeptides and provided
3.4. Covalent modification of estrone with RGD-octapeptides preventing bone loss
The effect of orally administration of
3.5. Covalent modification of estradiol with two RGD-octapeptides inhibiting bone turnover
Using succinyl group as the linker of the 17β-hydroxy and using carbonylmethyl group as the linker of the 3-hydroxy estradiol was simultaneously modified with RGD-tetrapeptides and provided
3.6. Covalent modification of estradiol with two RGD-octapeptides preventing bone loss
The effect of orally administration of
3.7. Covalent modification of estradiol with RGD-octapeptides inducing no endometrial cell hyperplasia
The effect of orally administration of
3.8. Covalent modification of estradiol with RGD-octapeptides having no thrombosis risk
The effect of orally administration of
3.9. Summary of covalent modification of estrogen with RGD-octapeptides
With RGD-octapeptides modifying one hydroxyl group of estradiol and estrone or with RGD-tetrapeptides simultaneously modifying two hydroxyl groups of estradiol resulted in 12 conjugates. On ovariotomy mouse model and at 110.3 nmol/kg of oral dose their anti-osteoporosis activities were significantly higher than that of estradiol and estrone themselves. In contrast to estradiol and estrone themselves, the anti-osteoporosis therapy of these conjugates induced no endometrial cell hyperplasia and thrombosis risk. Comparing to RGD-tetrapeptide modified estradiol and estrone the effective dose of RGD-octapeptide modified estradiol and estrone is 1000 folds lower. This means that the anti-osteoporosis efficacy of RGD-octapeptide modified estradiol and estrone is 1000 folds higher than that of RGD-tetrapeptide modified estradiol and estrone. Reasonably, this dramatically enhanced efficacy could attitude to the introduction of RGD-octapeptides. Furthermore, due to ovariotomy mouse model simulates the bone loss condition of postmenopausal women and high activity these RGD-octapeptides modified estradiol and estrone should be preferentially promising candidates for HRT use.
4. Direct covalent modification of androgen with RGD-tetrapeptides
In the improvements of the efficacy of HRT, the anti-osteoporosis efficacy of androgen is found to be higher than that of estrogen, inducing no endometrial cell hyperplasia and having no thrombosis risk. Particularly in the research of androgen, 17
4.1. Direct covalent modification of androgen with RGD-tetrapeptides inhibiting bone turnover
The direct covalent modification of the 17
4.2. Direct covalent modification of androgen with RGD-tetrapeptides preventing bone loss
The effect of oral administration of
4.3. Direct covalent modification of androgen with RGD-tetrapeptides increasing total vBMD
CT measured 3D bone geometry and the size-independent vBMD, as well as pQCT quantitatively measured 3D bone geometry and size-independent vBMD were used to represent the anti-osteoporosis efficacy of
4.4. Direct covalent modification of androgen with RGD-tetrapeptides increasing trabecular vBMD
Figure 17 indicates that the trabecular vBMD of the femurs of NS plus intramuscular administration of prednisone treated mice is significantly lower than that of the femurs of NS alone treated mice. This means that prednisone effectively induces the mice to decrease trabecular vBMD. The trabecular vBMDs of the femurs of oral administration of
4.5. Direct covalent modification of androgen with RGD-tetrapeptides inducing no endomtrial cell hyperplasia
The effect of oral administration of
4.6. Direct covalent modification of androgen with RGD-tetrapeptides having no thrombosis risk
The effect of oral administration of
4.7. Summary of direct covalent modification of androgen with RGD-tetrapeptides
RGD-octapeptides directly modifying the 17
5. Indirect covalent modification of androgen with RGD-tetrapeptides
For androgen a parallel covalent modification with the direct covalent modification is an indirect strategy. In brief, between the 17
5.1. Indirect covalent modification of androgen with RGD-tetrapeptides inhibiting bone turnover
The effect of oral administration of
5.2. Indirect covalent modification of androgen with RGD-tetrapeptides preventing bone loss
The effect of oral administration of
5.3. Indirect covalent modification of androgen with RGD-tetrapeptides increasing total vBMD
CT measured 3D bone geometry and the size-independent vBMD, as well as pQCT quantitatively measured 3D bone geometry and size-independent vBMD were used to represent the anti-osteoporosis efficacy of
5.4. Indirect covalent modification of androgen with RGD-tetrapeptides increasing trabecular vBMD
Figure 22 indicates that the trabecular vBMD of the femurs of NS plus intramuscular administration of prednisone treated mice is significantly lower than that of the femurs of NS alone treated mice. This means that prednisone effectively induces the mice to decrease trabecular vBMD. The trabecular vBMDs of the femurs of oral administration of
5.5. Indirect covalent modification of androgen with RGD-tetrapeptides inducing no endomtrial cell hyperplasia
The effect of oral administration of
5.6. Indirect covalent modification of androgen with RGD-tetrapeptides having no thrombosis risk
The effect of oral administration of
5.7. Summary of indirect covalent modification of androgen with RGD-tetrapeptides
RGD-tetrapeptides indirectly modifying the 17
6. Nano-structures of RGD-peptides modified estrogen and androgen
Self-organization or self-assembly practically leads to the formation of various ordered nanostructures in solution, at bulk state, and on a solid surface [34,35]. Numerous self-assembling substances, such as highly fluorinated amphiphilic molecules[36], amphiphilic triblock copolymers with polyrotaxane as a central block [37], amphiphilic dodecyl ester derivatives from aromatic amino acids [38], dendritic molecules [39], the shape anisotropy of non-spherical colloidal building blocks [40], alkylated polycyclic aromatic hydrocarbons [41], porphyrins, graphenes and fullerenes [42], were designed. Of the self-assembling molecules, peptides have been considered a set of particular substance [43-51]. In respect of the self-assembly the formation of nano-structure is an inherent property of organic compounds. In this context, the nano-structures of
6.1. Nano-aggregators from modification of 17β-hydroxy of estradiol with RGD-octapeptides
As explained by Figure 6, using succinyl group and RGD-octapeptides modifying the 17β-hydroxy of estradiol provides
6.2. Nano-aggregators from modification of 3-hydroxy of estradiol with RGD-octapeptides
As seen in Figure 6, carbonylmethyl and RGD-octapeptides modifying the 3-hydroxy of estradiol provides
6.3. TEM image of nano-globes of androgen having RGD-tetrapeptides modified 17β-hydroxy
The nano-structures of
6.4. SEM image of nano-globes of androgen having RGD-tetrapeptides modified 17β-hydroxy
The nano-structures of
6.5. TEM image of nano-globes of androgen having RGD-tetrapeptides and succinyl modified 17β-hydroxy
The TEM images (Figures 31-33) demonstrate that in water
6.6. SEM image of nano-globes of androgen having RGD-tetrapeptides and succinyl modified 17β-hydroxy
The SEM image (Figures 34-36) demonstrates that in solid state
6.7. Summary of the nano-structures of RGD-peptides modified sex hormones
In water RGD-peptides modified sex hormones generally formed diverse nano-species via self-assembly. Due to all non-covalent bond interactions could be involved into the self-assembly the size and the feature of the nano-species of RGD-peptides modified sex hormones clearly depend on the concentration of their aqueous solution. Similarly, due to all non-covalent bond interactions could be involved into the self-assembly the size and the feature of the nano-species usually depend on the chemical structures of the sex hormones and the sequence of the RGD-peptides. In addition, the RGD-peptides modified sex hormones possessed various anti-osteoporosis activities. Thus the feature and the size of their nano-species could be correlated with their anti-osteoporosis activities. Therefore by selecting the concentration and by modifying the chemical structure we are able to optionally get the desirable nano-structure and consequently to optionally get desirable anti-osteoporosis activity.
7. Conclusions
Secondary osteoporosis is common in premenopausal women with osteoporosis and in older men, and is a major problem in clinical practice. More than one third of women with postmenopausal osteoporosis have identifiable secondary causes that contribute to bone loss. The secondary causes of osteoporosis in older men account for 50% - 80% of the cases of bone loss leading to fracture. Besides, secondary osteoporosis is common in the patients treated with glucocorticoids and in prostate cancer patients receiving ADT in particular. Glucocorticoids are ubiquitously prescribed in the fields of rheumatology, respirology, neurology, hematology, dermatology, gastroenterology, and transplant medicine. Chronic exposure to pharmacological doses of glucocorticoids causes multiple deleterious effects on osteopenia, osteoporosis and bone fracture. Prostate cancer is one of the most common diseases in the older men. After the surgery or radiation therapy the male patients with localized or metastatic prostate cancer are generally given ADT. Though male patients on ADT usually have good prognosis, osteoporosis is a very common consequence of this therapy and up to 20% of the patients will fracture within 5 years. To prevent osteoporotic fracture in premenopausal women with osteoporosis, the female patients treated with glucocorticoids and the male patients receiving ADT RGD-peptides modified sex hormones were provided. On ovariotomy and prednisone induced osteoporosis mice either ip injection or orally dosed the modified hormones were able to enhance the efficacy and minimize the adverse effects. By forming nano-species their therapy could be further improved.
Acknowledgments
This work was finished in Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, supported by Innovation Platform Project of Education Committee of Beijing, Special Project (2011ZX09302-007-01), and Natural Scientific Foundation of China (81072522 and 81273379).References
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