The interaction of macrophages with micro and nano particles (MNPs) is important because these cells clear particles from the circulation, and because they are potential therapeutic targets in inflammatory conditions, atherosclerosis and cancer. Therefore, an understanding of the features of MNPs that influence their interaction with macrophages may allow optimization of their properties for enhanced drug delivery. In this study, we show that particle shape impacts phagocytosis by macrophages, and more importantly, that particle shape and size separately impact attachment and internalization. The study provides methodology for further exploring how particle shape can be controlled to achieve desired attachment and internalization. The results of the study also give mechanistic guidance on how particle shape can be manipulated to design drug carriers to evade macrophages, or alternatively to target macrophages.
Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma ( NCT01156584).
Abstract-An initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (M⌽). Because HDL does not interact with M⌽ ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester-loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase. T o remove cholesterol from the body, it must be dissolved into or converted to bile acids in the liver. This biliary excretion pathway is fed by the transport of cholesterol from peripheral tissues and is referred to as reverse cholesterol transport (RCT). An early step in RCT is the transfer of peripheral-cell unesterified cholesterol to plasma highdensity lipoproteins (HDLs). The HDLs serve as transport vehicles for excess cellular cholesterol through the plasma compartment to the liver. Importantly, the transfer of cellular cholesterol to HDL does not occur in plasma. It occurs in extracellular spaces, like the subendothelial space or intima of a vessel within an atherosclerotic lesion. We do not yet fully understand how apolipoprotein AI (apoAI) promotes the efficient transfer of excess cholesterol from peripheral cells [ie, intimal macrophage (M⌽) foam cells] to HDL. Convincing data have been published that in vivo apoAI participates in efficient free-cholesterol efflux from peripheral tissues, including atherosclerotic lesions. 1,2 There is no documented unique specificity for apoAI in mediating cellular cholesterol efflux in vitro, because many other exchangeable amphipathic alpha helical apoproteins can substitute for apoAI. Why is there specificity for apoAI in vivo in mediating efficient M⌽ cholesterol efflux from lesions? In this review, we wish to speculate that the in vivo efficiency of apoAI is a direct function of its ability to dissociate from spherical HDL and to form stable, lipid-poor apoAI, which can be rapidly lipidated with cellular M⌽ ATP binding cassette A1 (ABCA1)-transported free cholesterol and phospholipids. Multiple locally produced M⌽ liver X receptor (LXR)-regulated proteins probably participate in this interstitial remodeling of HDL to produce lipid-poor apoAI. Phospholipid transfer protein (PLTP) and cholesteryl ester (CE) transfer protein (CETP) are expressed by M⌽, can generate lipid-poor apoAI from spherical HDL, are present in lesions, and are induced by ligation of LXR. Thus, M⌽-expressed PLTP and CETP could promote M⌽ cholesterol efflux by generating ...
The Epic Platform was developed for the unbiased detection and molecular characterization of circulating tumour cells (CTCs). Here, we report assay performance data, including accuracy, linearity, specificity and intra/inter-assay precision of CTC enumeration in healthy donor (HD) blood samples spiked with varying concentrations of cancer cell line controls (CLCs). Additionally, we demonstrate clinical feasibility for CTC detection in a small cohort of metastatic castrate-resistant prostate cancer (mCRPC) patients. The Epic Platform demonstrated accuracy, linearity and sensitivity for the enumeration of all CLC concentrations tested. Furthermore, we established the precision between multiple operators and slide staining batches and assay specificity showing zero CTCs detected in 18 healthy donor samples. In a clinical feasibility study, at least one traditional CTC/mL (CK+, CD45-, and intact nuclei) was detected in 89 % of 44 mCRPC samples, whereas 100 % of samples had CTCs enumerated if additional CTC subpopulations (CK-/CD45- and CK+ apoptotic CTCs) were included in the analysis. In addition to presenting Epic Platform's performance with respect to CTC enumeration, we provide examples of its integrated downstream capabilities, including protein biomarker expression and downstream genomic analyses at single cell resolution.
Objective-Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI. Methods and Results-Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLrϪ/Ϫ) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks. Macrophage PLTP deficiency increased atherosclerosis in LDLrϪ/Ϫ mice with minimal changes in total plasma cholesterol levels. In contrast, the extent of atherosclerosis in msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg mice was not significantly different between groups that had received PLTPϪ/Ϫ or PLTPϩ/ϩ bone marrow. In vitro studies indicated that PLTP deficiency led to a significant decrease in ␣-tocopherol content and increased oxidative stress in bone marrow cells. Key Words: phospholipid transfer protein Ⅲ apolipoprotein AI Ⅲ atherosclerosis Ⅲ transgenic mice Ⅲ bone marrow transplant P hospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in phospholipid and vitamin E transfers among plasma lipoproteins as well as between lipoproteins and cell membranes. [1][2][3] In addition, PLTP participates in the formation of pre--highdensity lipoproteins (HDLs) that promote the efflux of excess cellular cholesterol 4 -6 via the ATP-binding cassette transporter A1 (ABCA1) pathway. 7 Recent in vivo studies of PLTP transgenic and PLTP knockout mice report that PLTP plays a role in the control of plasma levels of both HDLs and apolipoprotein B (apoB)-containing lipoproteins. 8 -11 Systemic PLTP deficiency is atheroprotective in different strains of hypercholesterolemic mice, and transgenic mice overexpressing human PLTP have an increased risk of atherosclerosis. 9,12,13 To further support a proatherogenic potential of plasma PLTP in vivo, a positive correlation between circulating PLTP and the risk of coronary artery disease is observed in humans. 14 These studies have emphasized the action of PLTP at the systemic level and suggest that its proatherogenicity is likely a result of its actions on circulating lipoproteins. Although the impact of systemic PLTP on lipoprotein metabolism and antioxidant potential was studied, its tissue-specific actions have not been addressed. Conclusions-OurPLTP is synthesized and secreted by most cell types in humans and mice, and although first described as a plasma protein, it was recently shown to be expressed in macrophages within the intima of human atherosclerotic arteries. 15 We and others reported that PLTP is synthesized and secreted by cultured macrophages, and that the gene is upregulated by liver X receptor (LXR) ligands. 15,16 Macrophages are ess...
Systemic phospholipid transfer protein (PLTP) is a recognized risk factor for coronary heart disease. In apolipoprotein E-deficient mice, systemic PLTP deficiency is atheroprotective, whereas PLTP overexpression is proatherogenic. As expected, we also observed significantly smaller lesions (P < 0.0001) in hypercholesterolemic double mutant low density lipoprotein receptor-deficient (LDLr(-/-)) PLTP-deficient (PLTP(-/-)) mice compared with LDLr(-/-) mice expressing systemic PLTP. To assess the specific contribution of only macrophage-derived PLTP to atherosclerosis progression, bone marrow transplantation was performed in LDLr(-/-) mice that also lacked systemic PLTP. Groups of double mutant PLTP(-/-)LDLr(-/-) mice were irradiated with 1,000 rad and injected with bone marrow (BM) cells collected from either PLTP(-/-) or wild-type mice. When fed a high-fat diet, BM cell expression of PLTP decreased plasma cholesterol of PLTP(-/-)LDLr(-/-) mice from 878 +/- 220 to 617 +/- 183 mg/dl and increased HDL cholesterol levels from 54 +/- 11 to 117 +/- 19 mg/dl. This decreased total plasma cholesterol and increased HDL cholesterol contributed to the significantly smaller atherosclerotic lesions in both aortas and heart sinus valves observed in these mice. Thus, unlike total systemic PLTP, locally produced macrophage-derived PLTP beneficially alters lipoprotein metabolism and reduces lesion progression in hyperlipidemic mice.
Macrophage foam cells are key components of atherosclerotic plaque and play an important role in the progression of atherosclerosis leading to plaque rupture and thrombosis. Foam cells are emerging as attractive targets for therapeutic intervention and for imaging the progression of disease. Therefore, designing nanoparticles (NPs) targeted to macrophage foam cells in plaque is of considerable therapeutic significance. Here we report the construction of an oligonucleotide functionalized NP system with high affinity for foam cells. Nanoparticles functionalized with a 23-mer poly-Guanine (polyG) oligonucleotide are specifically recognized by the scavenger receptors on lipid-laden foam cells in vitro and ex vivo. The enhanced uptake of polyG-functionalized NPs by foam cells is inhibited in the presence of acetylated-LDL, a known ligand of scavenger receptors. Since polyG oligonucleotides are stable in serum and are unlikely to induce an immune response, their use for scavenger receptor-mediated targeting of macrophage foam cells provides a strategy for targeting atherosclerotic lesions.
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