Abstract
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily, which is composed of secretory transporter proteins, and binds a wide variety of small hydrophobic molecules. Using this function, we have reported the feasibility of using L-PGDS as a novel drug delivery vehicle for poorly water-soluble drugs. In this study, we show the development of a drug delivery system using L-PGDS, one that enables the direct clinical use of 7-ethyl-10-hydroxy-camptothecin (SN-38), a poorly water-soluble anti-cancer drug. In the presence of 2 mM L-PGDS, the concentration of SN-38 in PBS increased 1,130-fold as compared with that in PBS. Calorimetric experiments revealed that L-PGDS bound SN-38 at a molecular ratio of 1:3 with a dissociation constant value of 60 μM. The results of an in vitro growth inhibition assay revealed that the SN-38/L-PGDS complexes showed high anti-tumor activity against 3 human cancer cell lines, i.e., Colo201, MDA-MB-231, and PC-3 with a potency similar to that of SN-38 used alone. The intravenous administration of SN-38/L-PGDS complexes to mice bearing Colo201 tumors showed a pronounced anti-tumor effect. Intestinal mucositis, which is one of the side effects of this drug, was not observed in mice administered SN-38/L-PGDS complexes. Taken together, L-PGDS enables the direct usage of SN-38 with reduced side effects.
Highlights
Most compounds that exhibit anti-tumor activities are known to be water-insoluble and to have severe side effects on normal tissues and organs, limiting their efficacy and clinical use of them [1]
We investigated the effect of Lipocalin-type prostaglandin D synthase (L-PGDS) on the solubility of SN-38, and examined the interaction between L-PGDS and SN-38 by using isothermal titration calorimetry (ITC) and small-angle X-ray scattering (SAXS)
When 2 mM L-PGDS was added to phosphate-buffered saline (PBS), the solubility of SN-38 increased up to 1,700 μM, which was 1,130-fold as compared with that in PBS
Summary
Most compounds that exhibit anti-tumor activities are known to be water-insoluble and to have severe side effects on normal tissues and organs, limiting their efficacy and clinical use of them [1]. Some common approaches to improve the solubility of anti-cancer drugs are the chemical modification of drugs and the usage of solubilizers such as organic solvents, surfactants, lipids, cyclodextrin, and pH modifiers. The chemical modification of drugs decreases their potency in many cases. The usage of solubilizers is limited due to their toxicity and tendency to cause drug instability. Drug delivery systems (DDSs) for poorly watersoluble anti-cancer drugs that make effective use of different types of nano-sized delivery.
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