Paclitaxel-lipoate (IDD-1040) is a conjugate formed by the chemical joining of the two compounds, by condensing a lipoic acid moiety to the C2′ of paclitaxel. IDD-1040 was evaluated for its anti-tumor activity and potential druggability, using an in vivo non-small-cell, lung cancer (NSCLC) xenograft mouse model. In the in vivo studies, IDD-1040 showed a maximum tolerated dose (MTD) of 250 mg/kg compared to paclitaxel (PTX), with an MTD of 20 mg/kg. Most interesting, IDD-1040 demonstrated higher anti-tumor activity, and its inhibitory activity on tumor volume (cell growth) was dose-dependent. That anti-tumor activity persisted for two weeks after cessation of IDD-1040 treatment, as opposed to PTX cessation, after which the tumor relapsed, confirming that IDD-1040 exhibits superior tumor inhibition. Similar to PTX treatment, no marked body weight decrease was observed during IDD-1040 treatment, indicating a low toxicity profile. The increase in animal body weight noted over time was due to the increasing weight of tumors, recorded in all the mouse test groups. The results also showed that mortality rate of mice was reduced by treatment with IDD-1040, more so than with PTX. Furthermore, in a preliminary study on the ex vivo distribution of IDD-1040, neutropenia was primarily concentrated in the liver 1 h after injection, and most of the drug was metabolized by the liver in 24 h. All of these results demonstrate IDD-1040’s great potential as a candidate drug for cancer treatment.

Oncology Letters

Expanding paclitaxel's therapeutic window: Investigating the pharmacokinetic, clinical formulation and mechanistic aspects of paclitaxel‑lipoate conjugate

Article

Author: Rayan, Anwar ; Falah, Mizied ; Zeidan, Mouhammad ; Rayan, Mahmoud ; Abu‑Lafi, Saleh

Paclitaxel (PTX) is among the most widely used antimicrotubular chemotherapy agents available from natural sources. It has a wide range of antitumor effectiveness, particularly against breast, ovarian and lung malignancies. IDD-1040 is a novel anticancer chemical conjugate that combines lipoic acid with PTX and demonstrates an anticancer efficiency superior to that of PTX alone. The aim of the present study was to investigate the analytical, formulation and pharmacokinetic aspects of IDD-1040, shedding light on its pharmacological behavior and the possible mechanisms underlying its enhanced anticancer activity. IDD-1040 was administered to mice as an intravenous bolus, and the pharmacokinetic parameters were determined over the following 7 days. The results revealed a total clearance of 1.689 l/h.kg, volume of distribution of 1.93 l/kg, average half-life of 1.14 h and terminal half-life of 8.64 h. Notably, the area under the curve of IDD-1040 was >14-fold higher than that of PTX, suggesting slower metabolism and that prodrug itself may have antitumor activity. An in vitro tubulin polymerization assay revealed distinct tubulin-binding characteristics for IDD-1040 compared with PTX. Due to the poor water solubility of IDD-1040, a formulation development experiment was conducted. In total, 31 formulations were prepared that became transparent when diluted with water. In addition, some formulations achieved a relatively high drug content (12 mg/g) without the use of surfactants. Moreover, they included fewer excipients compared with the formulations diluted with water, suggesting a promising approach for drug formulation. In summary, IDD-1040 exhibited extended circulation, efficient tissue distribution and reduced metabolite formation in vitro, warranting further exploration of its mechanisms of action and therapeutic potential. Future studies are recommended to assess the stability, pharmacokinetics and pharmacodynamics of these refined IDD-1040 formulations to gauge their suitability for clinical application.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	Israel	IDD Therapeutics Ltd.	-

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