Low-Density Lipoprotein as a Vehicle for Targeting Antitumor Compounds to Cancer Cells

Firestone, Raymond A.

doi:10.1021/bc00026a002

Cited by 219 publications

(175 citation statements)

References 125 publications

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“…Growing and dividing cells require cholesterol for membrane synthesis which is delivered by LDL (Goldstein et al, 1983). This accounts also for cancer cells where an increased LDL uptake in tumours with high metastatic potential and aggressive or undifferentiated character was found (Firestone, 1994). The elevated number of LDL receptors expressed on tumour cells has been exploited for the delivery of lipophilic drugs.…”

mentioning

confidence: 99%

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

1999

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Summary Low density lipoprotein (LDL) receptor-mediated uptake and cytotoxic effects of N 4 -octadecyl-1-β-D-arabinofuranosylcytosine (NOAC) were studied in Daudi lymphoma cells. NOAC was either incorporated into LDL or liposomes to compare specific and unspecific uptake mechanisms. Binding of LDL to Daudi cells was not altered after NOAC incorporation (K D 60 nM). Binding of liposomal NOAC was not saturable with increasing concentrations. Specific binding of NOAC-LDL to Daudi cells was five times higher than to human lymphocytes. LDL receptor binding could be blocked and up-or down-regulated. Co-incubation with colchicine reduced NOAC-LDL uptake by 36%. These results suggested that NOAC-LDL is taken up via the LDL receptor pathway. In an in vitro cytotoxicity test, the IC 50 of NOAC-LDL was about 160 µM, whereas with liposomal NOAC the IC 50 was 40 µM. Blocking the LDL receptors with empty LDL protected 50% of the cells from NOAC cytotoxicity. The cellular distribution of NOAC-LDL or NOAC-liposomes differed only in the membrane and nuclei fraction with 13% and 6% respectively. Although it is more convenient to prepare NOAC-liposomes as compared to the loading of LDL particles with the drug, the receptor-mediated uptake of NOAC-LDL provides an interesting rationale for the specific delivery of the drug to tumours that express elevated numbers of LDL receptors.

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confidence: 99%

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

1999

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“…The membrane associated protein ApoB100 mediates the recognition of LDLs receptors and the subsequent uptake into cells through receptor-mediated endocytosis [19]. Altered LDLR levels are found in a variety of pathological conditions (e.g., atherosclerosis) [20] and several tumors overexpress LDLRs to supply the high cholesterol demand of rapidly dividing cells [21]. In the literature there are many examples on the use of LDL as carriers for imaging agents to tumor cells (Table 1).…”

Section: Low Density Lipoproteins (Ldl)mentioning

confidence: 99%

Lipid-Based Nanoparticles in Cardiovascular Molecular Imaging

Crich

Alberti

Orio

et al. 2012

Curr Cardiovasc Imaging Rep

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Abstract.The Gd(III) complexes currently used as MRI contrast agents are hydrophilic agents that distribute in the vascular and extracellular compartments. The visualization of atherosclerotic plaques requires systems endowed with lipophilic characteristics. Several Gd(III) complexes bearing lipophilic substituents have been reported. Among them Gd(III) complexes containing one or two aliphatic chains appears particularly useful for the intended application. These amphiphilic Gd(III) complexes have been incorporated into various type of supramolecular adducts that ensure enough sensibility for their detection in MR images of atherosclerotic plaques. Much attention has been devoted to the use of HDL and LDL Gd-loaded particles. The presence of long aliphatic chain(s) promotes the spontaneous aggregation of these complexes to form micelles that may associate as such to the surface of HDL particles. It has been shown that the transfer of single amphiphilic complexes into the lipidic core of the particles is possible by de-assembling the micelles through the formation of "host-guest" adducts with cyclodextrin. Gd-loaded liposomes have also been successfully tested in plaque detection as well as perfluoronanoparticles loaded with CEST agents. 4Introduction.

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“…sLDL can be routinely produced [18] that is physicochemically [20] and biologically [21] equivalent to native LDL. In addition sLDL has been employed to incorporate a range of drug payloads [22,23] and along with LDL therefore represent a proven class of drug targeting vector [24].…”

Section: Introductionmentioning

confidence: 99%

Uptake of synthetic Low Density Lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Zhou

Hatziieremia

Elliott

et al. 2010

Journal of Controlled Release

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Chronic myeloid leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34 + 38 lo/-), are significantly lower than in CML progenitor cells (total CD34 + ) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34 + and primitive CD34 + 38 lo/-cells accumulated significantly higher levels of sLDL when compared with non-CML CD34 + cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication.

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Low-Density Lipoprotein as a Vehicle for Targeting Antitumor Compounds to Cancer Cells

Cited by 219 publications

References 125 publications

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

Lipid-Based Nanoparticles in Cardiovascular Molecular Imaging

Uptake of synthetic Low Density Lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

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