A Novel Paclitaxel Conjugate with Higher Efficiency and Lower Toxicity: A New Drug Candidate for Cancer Treatment.

Falah Falah,Rayan Rayan

doi:10.3390/ijms20194965

Abstract

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.

Highlights

Paclitaxel (PTX), known by its brand name as Taxol®, is a diterpenoid pseudoalkaloid that consists of a taxane ring and an N-benzoylphenylisoserine group
PTX’s characteristic structure is somewhat different from those of the other taxanes, due to a complex C-13 side chain attached to the taxane ring, which is important for its anti-tumor activity (Figure 1, left side)
This study aimed to explore the possible consideration of IDD-1040 as an anticancer drug candidate

Summary

Introduction

Paclitaxel (PTX), known by its brand name as Taxol®, is a diterpenoid pseudoalkaloid that consists of a taxane ring and an N-benzoylphenylisoserine group. It was first isolated from the tree bark of the Pacific yew, Taxus brevifolia, and continues to be largely used as an antitumor drug [1]. Preclinical studies have shown many promising results against many tumors, and due to its increasing demand, PTX is currently considered one of the most important anti-tumor drugs in clinical use. Js. eMdolt.oScti.r2e0a1t9n, 2o0n, x-sFmORalPlEcEeRllRluEVnIgEWcancer [2], cervical cancer [3], brain cancer [4], ovarian canc3erof[51]5, breast cancer [6], and other cancers

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