Dataset Information

Reconstitution of Low-Density Lipoproteins with Fatty Acids for the Targeted Delivery of Drugs into Cancer Cells.

ABSTRACT: Low-density lipoproteins (LDLs) are a class of nanocarriers for the targeted delivery of therapeutics into aberrant cells that overexpress the LDL receptor. A facile procedure is used for reconstituting the hydrophobic core of LDLs with a binary fatty acid mixture. Facilitated by the tumor targeting capability of the apolipoprotein, the reconstituted, drug-loaded LDLs can effectively target cancer cells that overexpress the LDL receptor while showing minor adverse impact on normal fibroblasts. According to a hypothesized mechanism, the reconstituted LDLs can also enable metabolism-triggered drug release while preventing the payloads from lysosomal degradation. This study demonstrates that LDLs reconstructed with fatty acids hold great promise to serve as effective and versatile nanocarriers for targeted cancer therapy.

SUBMITTER: Zhu C

PROVIDER: S-EPMC6554211 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Reconstitution of Low-Density Lipoproteins with Fatty Acids for the Targeted Delivery of Drugs into Cancer Cells.

Zhu Chunlei C Pradhan Pallab P Huo Da D Xue Jiajia J Shen Song S Roy Krishnendu K Xia Younan Y

Angewandte Chemie (International ed. in English) 20170724 35

Low-density lipoproteins (LDLs) are a class of nanocarriers for the targeted delivery of therapeutics into aberrant cells that overexpress the LDL receptor. A facile procedure is used for reconstituting the hydrophobic core of LDLs with a binary fatty acid mixture. Facilitated by the tumor targeting capability of the apolipoprotein, the reconstituted, drug-loaded LDLs can effectively target cancer cells that overexpress the LDL receptor while showing minor adverse impact on normal fibroblasts. A ...[more]

PMID: 28646542

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Project description:BackgroundHIV-infected patients develop multiple metabolic abnormalities including insulin resistance, lipodystrophy and dyslipidemia. Although progression of these disorders has been associated with the use of various protease inhibitors and other antiretroviral drugs, HIV-infected individuals who have not received these treatments also develop lipid abnormalities albeit to a lesser extent. How HIV alters lipid metabolism in an infected cell and what molecular changes are affected through protein interaction pathways are not well-understood.ResultsSince many genetic, epigenetic, dietary and other factors influence lipid metabolism in vivo, we have chosen to study genome-wide changes in the proteomes of a human T-cell line before and after HIV infection in order to circumvent computational problems associated with multiple variables. Four separate experiments were conducted including one that compared 14 different time points over a period of >3 months. By subtractive analyses of protein profiles overtime, several hundred differentially expressed proteins were identified in HIV-infected cells by mass spectrometry and each protein was scrutinized for its biological functions by using various bioinformatics programs. Herein, we report 18 HIV-modulated proteins and their interaction pathways that enhance fatty acid synthesis, increase low density lipoproteins (triglycerides), dysregulate lipid transport, oxidize lipids, and alter cellular lipid metabolism.ConclusionsWe conclude that HIV replication alone (i.e. without any influence of antiviral drugs, or other human genetic factors), can induce novel cellular enzymes and proteins that are significantly associated with biologically relevant processes involved in lipid synthesis, transport and metabolism (p = <0.0002-0.01). Translational and clinical studies on the newly discovered proteins may now shed light on how some of these proteins may be useful for early diagnosis of individuals who might be at high risk for developing lipid-related disorders. The target proteins could then be used for future studies in the development of inhibitors for preventing lipid-metabolic anomalies. This is the first direct evidence that HIV-modulates production of proteins that are significantly involved in disrupting the normal lipid-metabolic pathways.

Project description:In previous studies we have shown that in HepG2 cells, as compared with fibroblasts, the low-density lipoprotein (LDL) receptor is only weakly down-regulated upon incubation of the cells with LDL. To explain this difference in down-regulation of the LDL-receptor activity, we studied simultaneously the intracellular processing of 125I-labelled LDL in both cell lines. Upon incubation of HepG2 cells with 125I-LDL, the appearance of degradation products started at 90 min, whereas in fibroblasts this lag time was only 30 min. The degradation efficiency (representing the ratio degradation/cell association of LDL) in HepG2 was less than 50% of that in fibroblasts up to 5h of incubation at 37 degrees C. The longer lag time and low efficiency of the degradation of LDL in HepG2 cells were independent of the cell density. Pulse-chase experiments indicated that the internalization rate of surface-bound LDL in HepG2 cells is similar to that of fibroblasts. Endosomal loading of 125I-LDL by incubation at 18 degrees C for 4.5 h, followed by a shift to 37 degrees C, resulted in degradation of LDL within 30 min in fibroblasts, whereas in HepG2 cells the lag time of the degradation was 90 min. In parallel experiments using subcellular fractionation by Percoll-gradient centrifugation of homogenized cells and 125I-tyramine-cellobiose-labelled LDL, we observed that in both cell types LDL is equally rapidly shifted from a low- to a high-density compartment (within 15 min), representing the endosomal and the late-endosomal plus lysosomal compartment respectively. We conclude that in HepG2 cells the cell-bound LDL, upon internalization, goes through the intracellular itinerary at the same rate as in fibroblasts, but that either the fusion between late endosomes and lysosomes or the lysosomal degradation itself is proceeding at a lower efficiency. A low degradation rate of LDL may contribute to explain the relatively weak down-regulation of the LDL-receptor activity in HepG2 cells by LDL.

Dataset Information

Reconstitution of Low-Density Lipoproteins with Fatty Acids for the Targeted Delivery of Drugs into Cancer Cells.

Publications

Reconstitution of Low-Density Lipoproteins with Fatty Acids for the Targeted Delivery of Drugs into Cancer Cells.

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