The introduction of 2-Hydroxypropyl-β-cyclodextrin

Introduction

Cyclodextrins (CDs) are useful formulation vehicles, which increase the amount of drug that can be solubilised in aqueous vehicles, thus increasing the delivery of many useful medicinal agents to a biological system. Without a successful delivery system, many drugs could not be developed. Cyclodextrins are cyclic amylose-derived oligomers composed of varying α-1-4-linked glucose units. These glucose chains form a cone-like cavity into which compounds may enter and form a water-soluble complex and thus change the drug’s physical–chemical properties. The number of units determines the size of the cone-like cavity and its corresponding name. For example, the most common cyclodextrins used as formulation vehicles are α-, β- and γ-cyclodextrin, with the corresponding number of glucose units (α = 6, β = 7, γ = 8). Although similar in their unit make-up, these cyclodextrin molecules possess slightly different absorption rates, possibly due to differences in degradation processes. α-, β- and γ-cyclodextrins are all used successfully to incorporate drugs into aqueous vehicles, and their toxicity profile has been studied extensively. The toxicity profile of CDs can differ depending on the route of administration[1].

2-hydroxylpropyl-β-cyclodextrin (HP-β-CD), a hydroxyalkyl derivative, is an alternative to α-, β-, and γ-cyclodextrin. It has improved water solubility properties and may be slightly more toxicologically benign.

Uses

2-Hydroxypropyl-β-cyclodextrin is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. HP-β-CyD is available in registered oral, buccal, rectal, ophthalmic, and intravenous products. Oral and intravenous solutions containing HP-β-CyD in complex with itraconazole, a broad-spectrum triazole antifungal agent, are widely used. Furthermore, HP-β-CyD has recently been approved for treating Niemann-Pick Type C disease (NPC), a lysosomal lipid storage disorder[2].

Function

Retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes local accumulation of cholesterol, both extracellularly and intracellularly. 2-hydroxypropyl-β-cyclodextrin increases cholesterol solubility and cholesterol crystal dissolution and reduces the formation of cholesterol crystals in lesions, leading even to regression of atherosclerosis. Zimmer et al. investigated the efficacy of 2-hydroxypropyl-β-cyclodextrin in the apolipoprotein E (ApoE−/−) deficient mouse model of atherosclerosis. ApoE−/− mice were fed a cholesterol-rich diet and concomitantly received subcutaneously 2-hydroxypropyl-β-cyclodextrin or NaCl 0.9% as vehicle control for 8 weeks. The results showed that 2-hydroxypropyl-β-cyclodextrin treatment reduced the size of the atherosclerotic plaques and the cholesterol crystal load and also stimulated plaque regression even when the cholesterol-rich diet was continued, and the plasma cholesterol levels remained unchanged. 2-hydroxypropyl-β-cyclodextrin did not alter the plaque composition (such as cellularity and macrophage content). However, it reduced the aortic ROS production and the concentration of proinflammatory cytokines in plasma, revealing that 2-hydroxypropyl-β-cyclodextrin attenuated plaque inflammation. Thus, the ability of cyclodextrins to form soluble complexes with cholesterol, thereby increasing the solubility of cholesterol in aqueous solutions even by 150,000-fold, appears to have great potential to counteract the inflammatory process in atherosclerotic plaques[3].

2-hydroxypropyl-β-cyclodextrin not only bound to the extracellular cholesterol crystals but also acted on intracellular cholesterol crystals. Thus, fluorescent 2-hydroxypropyl-β-cyclodextrin rapidly entered the cultured macrophages, was concentrated intracellularly, and increased the dissolution of intracellular cholesterol crystals. 2-hydroxypropyl-β-cyclodextrin increased the production of oxysterols in the macrophages and promoted liver transcriptional reprogramming, which X receptor (LXR)-dependently increased efflux of cholesterol and caused anti-inflammatory effects. In vivo, this LXR agonistic effect of 2-hydroxypropyl-β-cyclodextrin was required for the reduction of atherosclerosis and inflammation and for augmentation of the reverse cholesterol transport. The authors also evaluated biopsy specimens derived from human carotid endarterectomies. As expected, incubation of human atherosclerotic plaques with 2-hydroxypropyl-β-cyclodextrin caused cholesterol transfer from the plaques to the incubation media. Furthermore, the production of 27-hydroxycholesterol in 2-hydroxypropyl-β-cyclodextrin-treated human plaques was increased, and upon incubation, this oxysterol was released into the incubation medium. Taken together, the above study showed that 2-hydroxypropyl-β-cyclodextrin can promote the regression of atherosclerosis via macrophage reprogramming.

Safe

HP-β-CyD induced apoptosis and G2/M cell-cycle arrest in vitro and prolonged survival (without severe toxicity) in murine leukemia models. The mechanisms by which HP-β-CyD induced apoptosis of cancer cells remain unclear. HP-β-CyD is well tolerated in most species and shows limited toxicity, depending on dose and route of administration. A study using acute intraperitoneal HP-β-CyD administration revealed that, in mice, up to 10,000 mg/kg HP-β-CyD is tolerable. Although CyD-induced hemolysis of human and rabbit red blood cells is well known, in the present study, neither single nor repeated HP-β-CyD administration resulted in hemolysis or anemia in mice. Furthermore, HP-β-CyD-induced lung toxicity, such as foamy macrophage infiltration, alveolitis, and pulmonary edema have been reported in several animal species. The lungs of mice treated with HP-β-CyD for 13 weeks did not exhibit any histologic changes compared with those of control mice. No severe adverse effects were reported in two patients with NPC who received infusions of HP-β-CyD over 2 years.

In conclusion, HP-β-CyD disrupts cholesterol homeostasis and inhibits the proliferation of leukemic cells by induction of apoptosis and cell-cycle arrest. Systemic HP-β-CyD administration has limited toxicity where examined. HP-β-CyD is also effective against mutated TKI-resistant clones and hypoxia-adapted cells, suggesting that HP-β-CyD has a broad anticancer effect irrespective of the cellular characteristics by modulating cholesterol homeostasis.

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