Effect of CD on the antiaging drug: rapamycin

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Rapamycin (also known as sirolimus) is a macrolide compound produced by the bacterium Streptomyces hygroscopicus. It is immunosuppressant used to prevent organ transplant rejection. Recently it was observed that rapamycin treatment increased the lifespan by 9 to 14% in aged mice and by 10 to 15% in young mice [1]. Studies with an animal more close to human, a nonhuman primate, the common marmoset have been also started [2].

The mechanism of antiaging effect is associated with inhibition of mammalian target of rapamycin, mTOR signaling pathway and autophagy activation. mTOR signaling regulates cellular processes such as sensing nutrients and making proteins. Autophagy is the cell cleaning process responsible for the destruction of also protein aggregates such as amyloid-b. Autophagy decreases with age leading to cellular and organ dysfunction and to various chronic and degenerative diseases [3].

Due to the anti-inflammatory, immunosuppressive, anti-migratory, and anti-proliferative properties as well as its capability of activating autophagy, rapamycin is also a promising antiatherosclerotic agent [4].


Chemical formula of rapamycin

Complexation of rapamycin with CDs

Both aqueous solubility and stability of rapamycin were improved in the presence of BCD[5]. Phase solubility diagrams indicated AL and AN type curves after 3-day and 7-day equilibration, respectively. NMR studies showed only partial inclusion. The inclusion complexes displayed precipitation after a longer period of equilibration.

The aqueous solution of rapamycin in the presence of GCD was stable for over 26 days [6]. Only GCD was able to stabilize rapamycin both in solid state and in solution while the rapamycin complexes with ACD and BCD were less stable. The water-soluble GCD complexes and their aqueous solutions useful for oral, ophthalmic, topical and parenteral application have been patented. Both the solubilizing and stabilizing effect of HPBCD was insignificant [7].

Water-soluble high molecular-weight ACD and BCD polymers were obtained by crosslinking with epichlorohydrin and then the polymers were acetalized and emulsified to get nanoparticles which showed sustained release (5–17 days) and anti-atherosclerotic efficacy of rapamycin in apolipoprotein E-deficient (ApoE−/−) mice [8], [9].

A Korean patent describes solid dispersion of rapamycin and other sparingly water-soluble drug useful as intravenous injection prepared by CD derivatives (HPBCD) by using supercritical fluid process without non-aqueous solvents [10].

The known adverse effects of rapamycin in long-term high dosing, especially the increased risk of infection due to immunosuppression, force the researchers to find rapamycin analogs. One of the possibilities could be a complex with carefully selected CD derivative. Hyperlipidemia, one of adverse effect of rapamycin treatment could be suppressed by CD. Some of the CD derivatives are also able to activate autophagy [11] through controlling cholesterol trafficking and this way even synergistic effect with rapamycin is conceivable.


[1] Harrison DE, Strong R, Sharp ZD, et al. (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460 (7253), 392–395. doi:10.1038/nature08221.

[2] Tardif S. et al. (2014) Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J. Gerontol. A Biol. Sci. Med. Sci. 70, 577–588. doi:10.1093/gerona/glu101

[3] Rubinsztein DC, Mariño G, Kroemer G. (2011) Autophagy and aging. Cell 146(5), 682–595. doi: 10.1016/j.cell.2011.07.030.

[4] Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AB (1996) Rapamycin inhibits vascular smooth muscle cell migration. J. Clin. Invest. 98, 2277-2283. doi: 10.1172/JCI119038

[5] Rouf, MA Bilensoy, E Vural, I Hincal, AA (2007) Inclusion complexation of rapamycin with beta-cyclodextrin to improve solubility and stability of the drug. Eur. J. Pharm. Sci. 32, Suppl. S S46-S47. doi: 10.1016/j.ejps.2007.05.100

[6] Mangia, A; Grisenti, P; Monti, R; Reza, E, Shahrzad; VE (2012) New water-soluble solid pharmaceutical inclusion complexes and their aqueous solutions for oral, ophthalmic, topical or parenteral use containing a macrolide and certain cyclodextrins. EP2402350

[7] Kim MS, Kim JS, Park HJ, Cho WK, Cha KH, Hwang SJ (2011) Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process. Int. J. Nanomedicine 6, 2997–3009. doi: 10.2147/IJN.S26546

[8] Zhang J, Jia Y, Li X, Hu Y, Li X (2011) Facile Engineering of Biocompatible Materials with pH-Modulated Degradability. Advanced Materials, 23(27), 3035–3040. doi:10.1002/adma.201100679

[9] Dou Y, Guo J, Chen Y, Han S et al. (2016) Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerotic activity of rapamycin via selectively inhibiting mTORC1 in mice. J. Contr. Rel. 235, 48–62. doi: 10.1016/j.jconrel.2016.05.049

[10] Woo JS, Kim YH, Kwon YJ (2006) Method for preparing solid dispersion of sparingly water-soluble drug useful as intravenous injection by using supercritical fluid process without nonaqueous solvents. KR 2006110915

[11] Fenyvesi É (2011) Cyclodextrin in autophagy, Cyclodextrin News, 30(11), 1–8. https://cyclolab.hu/userfiles/cdn_2016_nov.pdf

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