Evaluation in melanoma-bearing mice of an etoposide derivative associated to a cholesterol-rich nanoemulsion

Abstract

A cholesterol-rich nanoemulsion (LDE) may be used as a vehicle to target antineoplastic drugs against cancer cells. The association of an etoposide derivative to LDE is stable and retains the cytotoxic activity of etoposide. We have evaluated the toxicity and antitumoral action of this new preparation in-vivo. Melanoma-bearing mice and control mice were administered LDE-etoposide oleate or commercial etoposide, either with or without radioactive labelling. The maximum tolerated dose (MTD), tissue distribution, plasma decay curves, pharmacokinetic parameters and antitumoral activity were determined. Association to LDE drastically reduced the drug toxicity, since MTD was approximately five-fold greater than in commercial etoposide. LDE-etoposide oleate was concentrated four-fold in the tumour compared with the normal adjacent tissues, was removed faster from plasma in tumour-bearing mice than in controls, and remained in the bloodstream longer than commercial etoposide. The tumour growth inhibition rate and survival were greater in animals treated with LDE-etoposide oleate compared with commercial etoposide. However, increasing the dose from 17 to 85 M kg À1 did not result in further improvement of the antitumour action. The incorporation of etoposide oleate to LDE resulted in markedly reduced toxicity and superior antitumoral activity. LDE-etoposide oleate is a promising new weapon for cancer treatment.

Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

“…The novel formulation showed maximum tolerance dose and 50% lethal dose roughly five times that of the commercial etoposide formulation. 12,20 Moreover, the toxicity of LDE-etoposide was also tested in a small safety study in two patients with refractory lymphoma. In the etoposide, 300 mg/m 2 dose/3 weeks, administered over 6 cycles.…”

“…9,10 Association to LDE of drugs such as carmustine, etoposide, and paclitaxel pronouncedly reduces the toxicity of those agents while preserving or even increasing the antineoplastic activity, as shown in tumor-implanted rats and mice. [11][12][13] In a subsequent study, we showed that LDE can also concentrate in the lesioned aortas of cholesterol-fed rabbits after injection into the blood circulation. Treatment of the atherosclerotic rabbits with the association of paclitaxel to LDE resulted in marked reduction of the atherosclerotic lesions.…”

Intra-articular methotrexate associated to lipid nanoemulsions: anti-inflammatory effect upon antigen-induced arthritis

“…When antiproliferative agents, such as paclitaxel, carmustine, or etoposide were associated with LDE, they promoted inhibition of tumor growth in murine oncologic models and they also inhibited the development of atheromatous lesions in rabbits with induced atherosclerosis. [9][10][11][12][13] Association with LDE resulted in a remarkable reduction of the toxicity of those drugs.…”

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

“…As tested in mice, several formulations developed in our laboratory, such as the association of LDE with carmustine, with etoposide, with paclitaxel (PTX), and with daunorubicin had severalfold less toxicity than the corresponding commercial preparations, as analyzed by classic pharmacological parameters, such as maximum tolerated dose or median lethal dose (LD 50 ). [16][17][18][19][20][21] In pilot clinical trials performed in patients with advanced cancers, LDE-carmustine, LDE-etoposide, and LDE-PTX showed no observable clinical and laboratorial toxicities at doses corresponding to those used in routine cancer treatment. Because it is prepared only with lipids present in the organism, LDE has no immunogenic potential and no safety issues related to materials in the nanoemulsion composition.…”

“…As shown here and elsewhere in tumorbearing animals, the use of an LDE system had the ability to increase the effectiveness of carried chemotherapeutic agents, such as carmustine, etoposide, daunorubicin, and PTX, while drastically reducing their toxicity. 17,19,21,84 In pilot clinical trials performed in patients with advanced cancers, LDE-carmustine, LDE-etoposide, and LDE-PTX showed no observable clinical or laboratorial toxicities in doses corresponding to those used in routine cancer treatment. 5,14,23 Therefore, the LDE system and eventually others that explore the LDL-receptor endocytic pathways as drug-delivery gateway are creditable candidates for introduction in clinical oncology practice.…”