1. Influence of route of administration and lipidation of apolipoprotein A-I peptide on pharmacokinetics and cholesterol mobilization.
期刊:Journal of lipid research
日期:2016-11-23
DOI :10.1194/jlr.M071043
apoA-I, apoA-I mimetic peptides, and their lipid complexes or reconstituted high-density lipoprotein (HDL) have been studied as treatments for various pathologies. However, consensus is lacking about the best method for administration, by intravenous (IV) or intraperitoneal (IP) routes, and formulation, as an HDL particle or in a lipid-free form. The objective of this study was to systematically examine peptide plasma levels, cholesterol mobilization, and lipoprotein remodeling in vivo following administration of lipid-free apoA-I peptide (22A) or phospholipid reconstituted 22A-sHDL by IV and IP routes. The mean circulation half-life was longer for 22A-sHDL (T = 6.27 h) than for free 22A (T = 3.81 h). The percentage of 22A absorbed by the vascular compartment after the IP dosing was ∼50% for both 22A and 22A-sHDL. The strongest pharmacologic response came from IV injection of 22A-sHDL, specifically a 5.3-fold transient increase in plasma-free cholesterol (FC) level compared with 1.3- and 1.8-fold FC increases for 22A-IV and 22A-sHDL-IP groups. Addition of either 22A or 22A-sHDL to rat plasma caused lipoprotein remodeling and appearance of a lipid-poor apoA-I. Hence, both the route of administration and the formulation of apoA-I peptide significantly affect its pharmacokinetics and pharmacodynamics.
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1区Q1影响因子: 34.9
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2. Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging.
期刊:Nature nanotechnology
日期:2020-04-20
DOI :10.1038/s41565-020-0642-4
Ischaemic heart disease evokes a complex immune response. However, tools to track the systemic behaviour and dynamics of leukocytes non-invasively in vivo are lacking. Here, we present a multimodal hot-spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (F-HDL) to allow myeloid cell tracking by F magnetic resonance imaging. The F-HDL nanotracer can additionally be labelled with zirconium-89 and fluorophores to detect myeloid cells by in vivo positron emission tomography imaging and optical modalities, respectively. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo F-HDL magnetic resonance imaging. Concurrently, using ex vivo techniques, we showed that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and at the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox, enabling the study of complex myeloid cell behaviour dynamically.
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2区Q1影响因子: 6.5
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3. Characterization of apolipoprotein A-I peptide phospholipid interaction and its effect on HDL nanodisc assembly.
期刊:International journal of nanomedicine
日期:2019-04-30
DOI :10.2147/IJN.S179837
Synthetic HDLs (sHDLs), small nanodiscs of apolipoprotein mimetic peptides surrounding lipid bilayers, were developed clinically for atheroma regression in cardiovascular patients. Formation of HDL involves interaction of apolipoprotein A-I (ApoA-I) with phospholipid bilayers and assembly into lipid-protein nanodiscs. The objective of this study is to improve understanding of physico-chemical aspects of HDL biogenesis such as the thermodynamics of ApoA-I-peptide membrane insertion, lipid binding, and HDL self-assembly to improve our ability to form homogeneous sHDL nanodiscs that are suitable for clinical administration. The ApoA-I-mimetic peptide, 22A, was combined with either egg sphingomyelin (eSM) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid vesicles to form sHDL. The sHDL assembly process was investigated through lipid vehicle solubilization assays and characterization of purity, size, and morphology of resulting nanoparticles via gel permeation chromatography (GPC), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Peptide-lipid interactions involved were further probed by sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The pharmacokinetics of eSM-sHDL and POPC-sHDL nanodiscs were investigated in Sprague Dawley rats. sHDL formation was temperature-dependent, with spontaneous formation of sHDL nanoparticles occurring only at temperatures exceeding lipid transition temperatures as evidenced by DLS, GPC, and TEM characterization. SFG and ATR-FTIR spectroscopy findings support a change in peptide-lipid bilayer interactions at temperatures above the lipid transition temperature. Lipid-22A interactions were stronger with eSM than with POPC, which resulted in the formation of more homogeneous sHDL nanoparticles with longer in vivo circulation time as evidenced the PK study. Physico-chemical characteristics of sHDL are in part determined by phospholipid composition. Optimization of phospholipid composition may be utilized to improve the stability and homogeneity of sHDL.
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1区Q1影响因子: 16
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4. Single step reconstitution of multifunctional high-density lipoprotein-derived nanomaterials using microfluidics.
作者:Kim YongTae , Fay Francois , Cormode David P , Sanchez-Gaytan Brenda L , Tang Jun , Hennessy Elizabeth J , Ma Mingming , Moore Kathryn , Farokhzad Omid C , Fisher Edward Allen , Mulder Willem J M , Langer Robert , Fayad Zahi A
期刊:ACS nano
日期:2013-10-03
DOI :10.1021/nn4039063
High-density lipoprotein (HDL) is a natural nanoparticle that transports peripheral cholesterol to the liver. Reconstituted high-density lipoprotein (rHDL) exhibits antiatherothrombotic properties and is being considered as a natural treatment for cardiovascular diseases. Furthermore, HDL nanoparticle platforms have been created for targeted delivery of therapeutic and diagnostic agents. The current methods for HDL reconstitution involve lengthy procedures that are challenging to scale up. A central need in the synthesis of rHDL, and multifunctional nanomaterials in general, is to establish large-scale production of reproducible and homogeneous batches in a simple and efficient fashion. Here, we present a large-scale microfluidics-based manufacturing method for single-step synthesis of HDL-mimicking nanomaterials (μHDL). μHDL is shown to have the same properties (e.g., size, morphology, bioactivity) as conventionally reconstituted HDL and native HDL. In addition, we were able to incorporate simvastatin (a hydrophobic drug) into μHDL, as well as gold, iron oxide, quantum dot nanocrystals or fluorophores to enable its detection by computed tomography (CT), magnetic resonance imaging (MRI), or fluorescence microscopy, respectively. Our approach may contribute to effective development and optimization of lipoprotein-based nanomaterials for medical imaging and drug delivery.
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1区Q1影响因子: 16
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5. Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis.
作者:Beldman Thijs J , Senders Max L , Alaarg Amr , Pérez-Medina Carlos , Tang Jun , Zhao Yiming , Fay Francois , Deichmöller Jacqueline , Born Benjamin , Desclos Emilie , van der Wel Nicole N , Hoebe Ron A , Kohen Fortune , Kartvelishvily Elena , Neeman Michal , Reiner Thomas , Calcagno Claudia , Fayad Zahi A , de Winther Menno P J , Lutgens Esther , Mulder Willem J M , Kluza Ewelina
期刊:ACS nano
日期:2017-05-15
DOI :10.1021/acsnano.7b01385
Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received Zr-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP-immune cell interactions significantly decreased over the disease progression. Zr-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.
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1区Q1影响因子: 16
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6. Atherosclerotic plaque targeting mechanism of long-circulating nanoparticles established by multimodal imaging.
作者:Lobatto Mark E , Calcagno Claudia , Millon Antoine , Senders Max L , Fay Francois , Robson Philip M , Ramachandran Sarayu , Binderup Tina , Paridaans Maarten P M , Sensarn Steven , Rogalla Stephan , Gordon Ronald E , Cardoso Luis , Storm Gert , Metselaar Josbert M , Contag Christopher H , Stroes Erik S G , Fayad Zahi A , Mulder Willem J M
期刊:ACS nano
日期:2015-01-28
DOI :10.1021/nn506750r
Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
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1区Q1影响因子: 16
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7. Tumor Targeting by αβ-Integrin-Specific Lipid Nanoparticles Occurs Phagocyte Hitchhiking.
期刊:ACS nano
日期:2020-05-20
DOI :10.1021/acsnano.9b08693
Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for targeting mechanisms. Dynamic phenomena such as NPs' real-time targeting kinetics and phagocytes' contribution to active NP targeting remain largely unexplored. To better understand targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate positron emission tomography/computed tomography imaging with intravital microscopy and flow cytometric analyses to study αβ-integrin-targeted cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified "NP hitchhiking" with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies.
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1区Q1影响因子: 34.9
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8. Smart cancer nanomedicine.
期刊:Nature nanotechnology
日期:2019-11-06
DOI :10.1038/s41565-019-0567-y
Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies.
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2区Q1影响因子: 6.1
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9. Imaging-guided nanomedicine development.
期刊:Current opinion in chemical biology
日期:2021-03-15
DOI :10.1016/j.cbpa.2021.01.014
Nanomedicine research is an active field that produces thousands of studies every year. However, translation of nanotherapeutics to the clinic has yet to catch up with such a vast output. In recent years, the need to better understand nanomedicines' in vivo behavior has been identified as one of the major challenges for efficient clinical translation. In this context, noninvasive imaging offers attractive solutions to provide valuable information about nanomedicine biodistribution, pharmacokinetics, stability, or therapeutic efficacy. Here, we review the latest imaging approaches used in the development of therapeutic nanomedicines, discuss why these strategies bring added value along the translational pipeline, and give a perspective on future advances in the field.
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3区Q2影响因子: 3.8
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10. Probing the Assembly of HDL Mimetic, Drug Carrying Nanoparticles Using Intrinsic Fluorescence.
期刊:The Journal of pharmacology and experimental therapeutics
日期:2020-01-15
DOI :10.1124/jpet.119.262899
Reconstituted high-density lipoprotein (HDL) containing apolipoprotein A-I (Apo A-I) mimics the structure and function of endogenous (human plasma) HDL due to its function and potential therapeutic utility in atherosclerosis, cancer, neurodegenerative diseases, and inflammatory diseases. Recently, a new class of HDL mimetics has emerged, involving peptides with amino acid sequences that simulate the the primary structure of the amphipathic alpha helices within the Apo A-I protein. The findings reported in this communication were obtained using a similar amphiphilic peptide (modified via conjugation of a myristic acid residue at the amino terminal aspartic acid) that self-assembles (by itself) into nanoparticles while retaining the key features of endogenous HDL. The studies presented here involve the macromolecular assembly of the myristic acid conjugated peptide (MYR-5A) into nanomicellar structures and its characterization via steady-state and time-resolved fluorescence spectroscopy. The structural differences between the free peptide (5A) and MYR-5A conjugate were also probed, using tryptophan fluorescence, Fӧrster resonance energy transfer (FRET), dynamic light scattering, and gel exclusion chromatography. To our knowledge, this is the first report of a lipoprotein assembly generated from a single ingredient and without a separate lipid component. The therapeutic utility of these nanoparticles (due to their capablity to incorporate a wide range of drugs into their core region for targeted delivery) was also investigated by probing the role of the scavenger receptor type B1 in this process. SIGNIFICANCE STATEMENT: Although lipoproteins have been considered as effective drug delivery agents, none of these nanoformulations has entered clinical trials to date. A major challenge to advancing lipoprotein-based formulations to the clinic has been the availability of a cost-effective protein or peptide constituent, needed for the assembly of the drug/lipoprotein nanocomplexes. This report of a robust, spontaneously assembling drug transport system from a single component could provide the template for a superior, targeted drug delivery strategy for therapeutics of cancer and other diseases (Counsell and Pohland, 1982).
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1区Q1影响因子: 17.7
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11. High-Density Lipoprotein Nanobiologics for Precision Medicine.
期刊:Accounts of chemical research
日期:2017-12-27
DOI :10.1021/acs.accounts.7b00339
Nature is an inspirational source for biomedical engineering developments. Particularly, numerous nanotechnological approaches have been derived from biological concepts. For example, among many different biological nanosized materials, viruses have been extensively studied and utilized, while exosome research has gained much traction in the 21st century. In our body, fat is transported by lipoproteins, intriguing supramolecular nanostructures that have important roles in cell function, lipid metabolism, and disease. Lipoproteins' main constituents are phospholipids and apolipoproteins, forming a corona that encloses a hydrophobic core of triglycerides and cholesterol esters. Within the lipoprotein family, high-density lipoprotein (HDL), primarily composed of apolipoprotein A1 (apoA-I) and phospholipids, measuring a mere 10 nm, is the smallest and densest particle. Its endogenous character makes HDL particularly suitable as a nanocarrier platform to target a range of inflammatory diseases. For a decade and a half, our laboratories have focused on HDL's exploitation, repurposing, and reengineering for diagnostic and therapeutic applications, generating versatile hybrid nanomaterials, referred to as nanobiologics, that are inherently biocompatible and biodegradable, efficiently cross different biological barriers, and intrinsically interact with immune cells. The latter is facilitated by HDL's intrinsic ability to interact with the ATP-binding cassette receptor A1 (ABCA1) and ABCG1, as well as scavenger receptor type B1 (SR-BI). In this Account, we will provide an up-to-date overview on the available methods for extraction, isolation, and purification of apoA-I from native HDL, as well as its recombinant production. ApoA-I's subsequent use for the reconstitution of HDL (rHDL) and other HDL-derived nanobiologics, including innovative microfluidic-based production methods, and their characterization will be discussed. The integration of different hydrophobic and amphiphilic imaging labels, including chelated radioisotopes and paramagnetic or fluorescent lipids, renders HDL nanobiologics suitable for diagnostic purposes. Nanoengineering also allows HDL reconstitution with core payloads, such as diagnostically active nanocrystals, as well as hydrophobic drugs or controlled release polymers for therapeutic purposes. The platform technology's specificity for inflammatory myeloid cells and methods to modulate specificity will be highlighted. This Account will build toward examples of in vivo studies in cardiovascular disease and cancer models, including diagnostic studies by magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). A translational success story about the escalation of zirconium-89 radiolabeled HDL (Zr-HDL) PET imaging from atherosclerotic mice to rabbits and pigs and all the way to cardiovascular disease patients is highlighted. Finally, recent advances in nanobiologic-facilitated immunotherapy of inflammation are spotlighted. Lessons, success stories, and perspectives on the use of these nature-inspired HDL mimetics are an integral part of this Account.
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1区Q1影响因子: 25.7
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12. Nanotechnology for cardiovascular diseases.
期刊:Innovation (Cambridge (Mass.))
日期:2022-02-02
DOI :10.1016/j.xinn.2022.100214
Cardiovascular diseases have become the major killers in today's world, among which coronary artery diseases (CADs) make the greatest contributions to morbidity and mortality. Although state-of-the-art technologies have increased our knowledge of the cardiovascular system, the current diagnosis and treatment modalities for CADs still have limitations. As an emerging cross-disciplinary approach, nanotechnology has shown great potential for clinical use. In this review, recent advances in nanotechnology in the diagnosis of CADs will first be elucidated. Both the sensitivity and specificity of biosensors for biomarker detection and molecular imaging strategies, such as magnetic resonance imaging, optical imaging, nuclear scintigraphy, and multimodal imaging strategies, have been greatly increased with the assistance of nanomaterials. Second, various nanomaterials, such as liposomes, polymers (PLGA), inorganic nanoparticles (AuNPs, MnO, etc.), natural nanoparticles (HDL, HA), and biomimetic nanoparticles (cell-membrane coating) will be discussed as engineered as drug (chemicals, proteins, peptides, and nucleic acids) carriers targeting pathological sites based on their optimal physicochemical properties and surface modification potential. Finally, some of these nanomaterials themselves are regarded as pharmaceuticals for the treatment of atherosclerosis because of their intrinsic antioxidative/anti-inflammatory and photoelectric/photothermal characteristics in a complex plaque microenvironment. In summary, novel nanotechnology-based research in the process of clinical transformation could continue to expand the horizon of nanoscale technologies in the diagnosis and therapy of CADs in the foreseeable future.
作者:Kuai Rui , Li Dan , Chen Y Eugene , Moon James J , Schwendeman Anna
期刊:ACS nano
日期:2016-02-25
DOI :10.1021/acsnano.5b07522
High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well-known as the "good" cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and antioxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, and inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultrasmall size (8-12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12-24 h), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to those of endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize (a) clinical pharmacokinetics and safety of reconstituted HDL products, (b) comparison of HDL with inorganic and other organic nanoparticles,
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1区Q1影响因子: 12.5
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14. Lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy.
期刊:Science advances
日期:2024-03-13
DOI :10.1126/sciadv.adk2444
Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.