Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS dbdb (diabetes), and eNOS dbdb treated with rHDL (diabetes+rHDL) with both males and females were used.

Photophysical Characterization and In Vitro Evaluation of α-Mangostin-Loaded HDL Mimetic Nano-Complex in LN-229 Glioblastoma Spheroid Model.

Cytotoxic activity has been reported for the xanthone α-mangostin (AMN) against Glioblastoma multiforme (GBM), an aggressive malignant brain cancer with a poor prognosis. Recognizing that AMN's high degree of hydrophobicity is likely to limit its systemic administration, we formulated AMN using reconstituted high-density lipoprotein (rHDL) nanoparticles. The photophysical characteristics of the formulation, including fluorescence lifetime and steady-state anisotropy, indicated that AMN was successfully incorporated into the rHDL nanoparticles.

A Spontaneous Assembling Lipopeptide Nanoconjugate Transporting the Anthracycline Drug -Benzyladriamycin-14-valerate for Personalized Therapy of Ewing Sarcoma.

To meet the current need for a tumor-selective, targeted therapy regimen associated with reduced toxicity, our laboratory has developed a nanostructure that resembles high-density lipoproteins (HDLs). These myristoyl-5A (MYR-5A) nanotransporters are designed to safely transport lipophilic pharmaceuticals, including a novel anthracycline drug (-benzyladriamycin-14-valerate (AD198)). This formulation has been found to enhance the therapeutic efficacy and reduced toxicity of drugs in preclinical studies of 2D and 3D models of Ewing sarcoma (EWS) and cardiomyocytes.

Mannose-Coated Reconstituted Lipoprotein Nanoparticles for the Targeting of Tumor-Associated Macrophages: Optimization, Characterization, and In Vitro Evaluation of Effectiveness.

Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been utilized as delivery vehicles to a variety of targets, including cancer cells. However, the modification of rHDL NPs for the targeting of the pro-tumoral tumor-associated macrophages (TAMs) remains largely unexplored. The presence of mannose on nanoparticles can facilitate the targeting of TAMs which highly express the mannose receptor at their surface.

Lipoproteins and the Tumor Microenvironment.

The tumor microenvironment (TME) plays a key role in enhancing the growth of malignant tumors and thus contributing to "aggressive phenotypes," supporting sustained tumor growth and metastasis. The precise interplay between the numerous components of the TME that contribute to the emergence of these aggressive phenotypes is yet to be elucidated and currently under intense investigation. The purpose of this article is to identify specific role(s) for lipoproteins as part of these processes that facilitate (or oppose) malignant growth as they interact with specific components of the TME during tumor development and treatment.

Probing the Assembly of HDL Mimetic, Drug Carrying Nanoparticles Using Intrinsic Fluorescence.

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.

Identifying and targeting angiogenesis-related microRNAs in ovarian cancer.

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach.

The SR-B1 Receptor as a Potential Target for Treating Glioblastoma.

Purpose: The goal of these studies was to provide proof of concept for a novel targeted therapy for . These studies involve the evaluation of reconstituted high density lipoprotein (rHDL) nanoparticles (NPs) as delivery agents for the drug, mammalian Target of Rapamycin (mTOR) inhibitor Everolimus (EVR) to GBM cells. Cytotoxicity studies and assessment of downstream effects, including apoptosis, migration, and cell cycle events, were probed, in relation to the expression of scavenger receptor B type 1 (SR-B1) by GBM cells.

[Tc-HYNIC-N-dodecylamide]: a new hydrophobic tracer for labelling reconstituted high-density lipoproteins (rHDL) for radioimaging.

Despite the widespread use of nanotechnology in radio-imaging applications, lipoprotein based delivery systems have received only limited attention so far. These studies involve the synthesis of a novel hydrophobic radio-imaging tracer consisting of a hydrazinonicotinic acid (HYNIC)-N-dodecylamide and 99mTc conjugate that can be encapsulated into rHDL nanoparticles (NPs). These rHDL NPs can selectively target the Scavenger Receptor type B1 (SR-B1) that is overexpressed on most cancer cells due to excess demand for cholesterol for membrane biogenesis and thus can target tumors in vivo.

Reconstituted HDL: Drug Delivery Platform for Overcoming Biological Barriers to Cancer Therapy.

Drug delivery to malignant tumors is limited by several factors, including off-target toxicities and suboptimal benefits to cancer patient. Major research efforts have been directed toward developing novel technologies involving nanoparticles (NPs) to overcome these challenges. Major obstacles, however, including, opsonization, transport across cancer cell membranes, multidrug-resistant proteins, and endosomal sequestration of the therapeutic agent continue to limit the efficiency of cancer chemotherapy.

Lipoproteins for therapeutic delivery: recent advances and future opportunities.

The physiological role(s) of mammalian plasma lipoproteins is to transport hydrophobic molecules (primarily cholesterol and triacylglycerols) to their respective destinations. Lipoproteins have also been studied as drug-delivery agents due to their advantageous payload capacity, long residence time in the circulation and biocompatibility. The purpose of this review is to briefly discuss current findings with the focus on each type of formulation's potential for clinical applications.

Ultrasound-Stimulated Drug Delivery Using Therapeutic Reconstituted High-Density Lipoprotein Nanoparticles.

The abnormal tumor vasculature and the resulting abnormal microenvironment are major barriers to optimal chemotherapeutic drug delivery. It is well known that ultrasound (US) can increase the permeability of the tumor vessel walls and enhance the accumulation of anticancer agents. Reconstituted high-density lipoproteins (rHDL) nanoparticles (NPs) allow selective delivery of anticancer agents to tumor cells via their overexpressed scavenger receptor type B1 (SR-B1) receptor.

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion.

Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers.

SR-B1-targeted nanodelivery of anti-cancer agents: a promising new approach to treat triple-negative breast cancer.

Patients with triple-negative breast cancer (TNBC) have a considerably less favorable prognosis than those with hormone-positive breast cancers. TNBC patients do not respond to current endocrine treatment and have a 5-year survival prognosis of <30%. The research presented here is intended to fill a void toward the much needed development of improved treatment strategies for metastatic TNBC.

Fluorescence properties of doxorubicin in PBS buffer and PVA films.

We studied steady-state and time-resolved fluorescence properties of an anticancer drug Doxorubicin in a saline buffer and poly-vinyl alcohol (PVA) film. Absorption of Doxorubicin, located at blue-green spectral region, allows a convenient excitation with visible light emitting diodes or laser diodes. Emission of Doxorubicin with maximum near 600nm can be easily detected with photomultipliers and CCD cameras.

Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.

Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles.

Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging.

Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins.

HDL as a drug and nucleic acid delivery vehicle.

This review is intended to evaluate the research findings and potential clinical applications of drug transport systems, developed based on the concepts of the structure/function and physiological role(s) of high density lipoprotein type nanoparticles. These macromolecules provide targeted transport of cholesteryl esters (a highly lipophilic payload) in their natural/physiological environment. The ability to accommodate highly water insoluble constituents in their core regions enables High density lipoproteins (HDL) type nanoparticles to effectively transport hydrophobic drugs subsequent to systemic administration.

A homodimeric BODIPY rotor as a fluorescent viscosity sensor for membrane-mimicking and cellular environments.

Fluorescence properties of a novel homodimeric BODIPY dye rotor for Fluorescence Lifetime Imaging Microscopy (FLIM) are reported. Steady state and time resolved fluorescence measurements established the viscosity dependent behaviour in vitro. Homodimeric BODIPY embedded in different membrane mimicking lipid vesicles (DPPC, POPC and POPC plus cholesterol) is demonstrated to be a viable sensor for fluorescence lifetime based viscosity measurements.

Targeted nanoparticles for pediatric leukemia therapy.

The two major forms of leukemia, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), account for about one-third of the malignancies diagnosed in children. Despite the marked successes in ALL and AML treatment, concerns remain regarding the occurrence of resistant disease in subsets of patients, the residual effects of therapy that often persist for decades beyond the cessation of treatment. Therefore, new approaches are needed to reduce or to avoid off target toxicities, associated with chemotherapy and their long-term residual effects.

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (NB) (HRNB). The long term survival rates of HRNB in the United States are still only 30-50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment.

The potential role of nanotechnology in therapeutic approaches for triple negative breast cancer.

Triple Negative Breast Cancer, TNBC, a highly aggressive and metastatic type of breast cancer, is characterized by loss of expression of the estrogen receptor (ER), progesterone receptor (PR), and a lack of overexpression of the human epidermal growth factor receptor 2 (HER2). It is a heterogeneous group of tumors with diverse histology, molecular uniqueness and response to treatment. Unfortunately, TNBC patients do not benefit from current anti-HER2 or hormone positive targeted breast cancer treatments; consequently, these patients rely primarily on chemotherapy.

The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics.

While the unique metabolic activities of malignant tissues as potential targets for cancer therapeutics has been the subject of several recent reviews, the role of cholesterol metabolism in this context is yet to be fully explored. Cholesterol is an essential component of mammalian cell membranes as well as a precursor of bile acids and steroid hormones. The hypothesis that cancer cells need excess cholesterol and intermediates of the cholesterol biosynthesis pathway to maintain a high level of proliferation is well accepted, however the mechanisms by which malignant cells and tissues reprogram cholesterol synthesis, uptake and efflux are yet to be fully elucidated as potential therapeutic targets.

Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics.

Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy.