Cyclodextrin polymer of reduced ototoxicity improves atherosclerosis therapy

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Although CD has been engineered into various nano-sized formulations, their main role was to incorporate a drug of interest for drug delivery and they were not regarded as therapeutic agents themselves. Kim et al. recently showed that the cyclodextrin polymer (CDP) prepared by covalent crosslinking of CD molecules (the product of CycloLab) improves pharmacokinetics and plaque targeting, and reduces plasma membrane disruption compared to CD, thus enabling effective and safe CD-based treatment of atherosclerosis. [1] The effects are summarized in Fig. 1

polym_atheroscl.png

Fig. 1 βCDP is not eliminated through the kidney due to its high size, it is accumulated in the atherosclerotic plaques and removes both intra- and extracellular cholesterol from the plaques while exhibiting reduced cholesterol removal from the cell membrane resulting in reduced ototoxicity, typical side effect for non-polymer CDs.

Cyanine7 was coupled to carboxymethyl BCD (CMβCD) and its epichlorohydrin-crosslinked polymer (CMβCDP) (Cy7-CD and Cy7-CDP).

Biodistributions of Cy7-CD and Cy7-CDP revealed that Cy7-CDP was cleared out mainly in the liver, while most of Cy7-CD was cleared in kidneys due to the size difference. (The mean hydrodynamic size of βCDP was measured to be 10.6 ± 0.7 nm in the DLS measurements). The bioavailabilities of Cy7-CD and Cy7-CDP after subcutaneous injection were measured to be 97.2 ± 3.5% and 93 ± 1.7%, respectively.

Both cholesterol solubilizing effect and the ability to remove crystalline cholesterol from macrophages of  βCDP is comparable to that of MβCD (RAMEB) and much higher than those of HPβCD (Fig. 2).

cholestFig. 2 Cholesterol dissolution of various CDPs and CDs (chart on the left). Dose-dependent effects of various CDPs and CDs on intracellular cholesterol removal in crystalline cholesterol-laden macrophages

Ex vivo culture of atherosclerotic plaques dissected from mice previously injected once with either HPβCD for 24 hours or βCDP for 72 hours at a dose of 1 g CD/kg showed that βCDP induced superior cholesterol efflux from plaque tissue. In addition, βCDP treatment did not affect plasma cholesterol and liver-associated enzyme levels and body weight. These results suggest that βCDP can exert greater therapeutic effects for the treatment of atherosclerosis without significant systemic toxicity than HPβCD.

Mice were given a single injection of HPβCD or βCDP at a dose of 8 g CD/kg that is known to cause ototoxicity in mice [15], and sacrificed for analysis one week after injection. While the mice treated with HPβCD exhibited significant loss of outer hair cells (OHC) in the mid-to-basal regions of the cochlea, the mice treated with βCDP showed no significant OHC loss.

The polymeric formulation of CD enhances therapeutic efficacy and results in reduced ototoxicity compared to CD and support the feasibility of CD-based therapy for the treatment of atherosclerosis.

[1] H. Kim, J. Han and J.-H. Park, Cyclodextrin polymer improves
atherosclerosis therapy and reduces ototoxicity, Journal of Controlled Release (2019),
https://doi.org/10.1016/j.jconrel.2019.12.021

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