Low Density Lipoprotein as a Carrier of Cytostatics in Cancer Chemotherapy: Study of Stability of Drug-carrier Complexes in Blood

Abstract

Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL. In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.

Interaction of rifampicin embedded in phospholipid nanoparticles with blood plasma lipoproteins

“…Такой подход описан в литературе для повышения доставки некоторых лекарств, в частности, противоопухолевых -за счёт их связывания с липопротеинами низкой плотности (ЛНП) [6][7][8]. Это может быть в принципе применено и для противотуберкулёзных препаратов, в частности, для рифампицина.…”

“…В частности, полагают возможность совместного транспорта с помощью этих белков липофильного лекарства вместе с фосфолипидами из частицы-переносчика к ЛВП или/и вместе с этерифицированным холестерином из ЛВП к ЛОНП и ЛНП [17]. В большинстве случаев такое перераспределение лекарств, например, противоопухолевых и противовоспалительных, сопровождается повышением их фармакологической эффективности за счёт появления возможности рецепторного взаимодействия с клеткой-мишенью [7,16]. Для рифампицина имеются лишь данные о его ассоциации с альфа-1-кислым гликопротеином, причём показано, что у больных туберкулёзом она может увеличиться за счёт гликозилирования белка [18].…”

Novel formulation of a methotrexate derivative with a lipid nanoemulsion

“…10 The use of a solid lipid nanoparticle system as a methotrexate carrier was reportedly shown to improve drug pharmacokinetics and to achieve regression of Ehrlich ascites carcinoma in mice. 11,12 The demonstration by Ho et al 13 that low-density lipoprotein receptors are overexpressed in neoplastic cells, paved the way for the use of lipoproteins [14][15][16][17] and subsequently of lipoprotein-like nanoemulsions 18,19 as vehicles to concentrate chemotherapeutic agents in neoplastic tissues. Taking this approach, the low-density lipoprotein receptor-mediated endocytic pathway is used to internalize drug-loaded lipid particles.…”

“…Taking this approach, the low-density lipoprotein receptor-mediated endocytic pathway is used to internalize drug-loaded lipid particles. [14][15][16][17] We showed that cholesterol-rich nanoemulsions, with a lipid structure mimicking low-density lipoprotein, has the ability to bind to low-density lipoprotein receptors. A lipid nanoemulsion is made without protein but, in contact with plasma, acquires apolipoprotein E, which is recognized by low-density lipoprotein receptors.…”

Captação pelo carcinoma de mama e pelo linfonodo axilar de uma nanoemulsão lipídica administrada por injeção no tecido mamário locorregional

“…O uso de LDL como agente direcionador de fármacos para as células neoplásicas tem sido explorado desde meados dos anos 1980 por diversos grupos (Rudling et al, 1983;Tokui et al, 1995;De Smidt & Van Berkel, 1990;Lundberg, 1987;Samadi-Baboli et al, 1993;Xiao et al, 1999) (De Smidt & Van Berkel, 1990 Atualmente existem vários estudos sobre a associação bem sucedida de antineoplásicos à LDL, dentre os quais se destacam a doxorrubicina (Chu et al, 2001;Kader et al, 1998), os derivados lipofílicos da daunorrubicina (Verluis et al, 1996) e os derivados lipofilícos da adriamicina (Masquelier et al, 2000). Também já foi demonstrada a incorporação de radiofármaco hidrofóbico marcado com I 125 captado pelos rLDL em três linhagens de tumores cervicais humanos (Xiao et al, 1999 Mesmo sem conter a proteína da LDL, a LDE entra em contato com as lipoproteínas naturais ao ser injetada na circulação plasmática e adquire a apoE, que pode ser reconhecida pelo rLDL.…”