Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel

Abstract

A cholesterol-rich emulsion (LDE) is taken up by malignant cells which over-express low-density lipoprotein (LDL) receptors and thus may be used as a carrier for drugs directed against neoplastic cells. In this study, we associated the antineoplastic agent paclitaxel to LDE and analysed the new formulation's incorporation efficiency, chemical and physical stability, cellular uptake and cytostatic activity against a neoplastic cell line and the acute toxicity to rats. A paclitaxel incorporation efficiency of approximately 75% was achieved when paclitaxel was mixed with LDE at a 6:1 lipid-to-drug molar ratio. The association of paclitaxel with LDE increased by 54% the mean diameter of the emulsion particles but did not damage the paclitaxel chemical structure as analysed by HPLC. Results from gradient ultracentrifugation and Sephadex G25 gel filtration indicated that the binding of the drug to the emulsion was stable. It was shown that the cellular uptake and the cytotoxic activity of LDE-paclitaxel by a neoplastic cell line (NCI-H292 cells) was indeed mediated by the LDL receptors. The antiproliferative activity of LDE-paclitaxel against NCI-H292 cells was less than that of a commercial paclitaxel preparation (50% inhibitory concentration, IC50 = 2.60 and 0.45 microM, respectively). This difference, however, can be ascribed to the in-vitro anti-proliferative activity of the commercial paclitaxel vehicle Cremophor EL; when Cremophor EL was added to the cultures with LDE-paclitaxel, the IC50 value was reduced to 0.45 microM, attaining that of the commercial paclitaxel preparation. The tolerability of LDE-paclitaxel in rats was remarkable, such that its lethal dose (LD50) was ten-fold greater than that of the commercial formulation (LD50 = 324 and 31.8 mg kg(-1), respectively). Therefore, LDE-paclitaxel association is stable and the cytostatic activity of the drug is preserved while its toxicity to rats is small. By diminishing the side effects and directing paclitaxel to neoplastic tissues, LDE may be useful as adjuvant in chemotherapy with this drug.

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

“…[13][14][15] To increase the yield of association with LDEs of those compounds and the stability of the preparations, an oleyl group was added to the molecular structure of the drugs, resulting in more lipophilic derivatives. [16][17][18][19] A prominent aspect of the LDEchemotherapeutic agent formulations is a remarkable reduction in drug toxicity.…”

Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

“…LDE, consisting of a cholesteryl ester core coated with a monolayer of phospholipids, resembles the LDL lipid-portion structure and has the ability to bind to LDLR on the cancer cell surface. [21][22][23][24][25] Although LDE has been confirmed with tumor-targeting effects mediated by LDLR and shows good drug-loading capacity of paclitaxel (PTX), it is stable for only 8 days at 4°C. 21 The instability of LDE-PTX, which might be attributable to the poor lipophilicity of PTX, 22 makes it less promising for clinical application.…”

“…[21][22][23][24][25] Although LDE has been confirmed with tumor-targeting effects mediated by LDLR and shows good drug-loading capacity of paclitaxel (PTX), it is stable for only 8 days at 4°C. 21 The instability of LDE-PTX, which might be attributable to the poor lipophilicity of PTX, 22 makes it less promising for clinical application. Alternatively, a novel lipid emulsion, which was composed of a PTX-CH complex surrounded by a phospholipid monolayer, was developed in our previous work ( Figure 1).…”

“…Alternatively, a novel lipid emulsion, which was composed of a PTX-CH complex surrounded by a phospholipid monolayer, was developed in our previous work ( Figure 1). 26 Compared with the tumor-targeting LDE-PTX loaded with PTX and cholesteryl ester reported previously, 21 substitution of the PTX-CH complex for PTX and cholesteryl ester of LDE-PTX has the following advantages: the PTX-CH complex not only greatly improves PTX solubility in the oil phase but can also function as a component of LDL-CH. 27 The resulting lipid emulsion (PTX-CH Emul) exhibits an ideal particle size, high drug-loading capability, high drugencapsulation efficiency, and excellent stability (12 months at 6°C).…”

Efeitos da associação de quimioterápicos na regressão de placa aterosclerótica e no perfil de marcadores inflamatórios em coelhos

“…Quando utilizado combinado com PTX, a LDE também manteve esses resultados, mantendo a atividade citotóxica ao mesmo tempo em que reduziu os efeitos colaterais em comparação com a preparação comercial do fármaco (Rodrigues & Maranhão, 2002). Houve, no entanto, uma alteração na estrutura de PTX para torná-lo mais estável e mais lipofílico, havendo transformação do taxol em oleato de paclitaxel pela ligação de ácidos graxos à sua molécula (Rodrigues & Maranhão, 2005).…”