Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis.

BACKGROUNDAntigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance.

Tolerance induction by liposomes targeting a single CD8 epitope IGRP in a model of type 1 diabetes is impeded by co-targeting a CD4 islet epitope.

The autoimmune disease type 1 diabetes is predominantly mediated by CD8 cytotoxic T-cell destruction of islet beta cells, of which islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is a dominant target antigen specificity. Previously, we found that a liposome-based antigen-specific immunotherapy encapsulating the CD4 T-cell islet epitope 2.5 together with the nuclear factor-κB inhibitor calcitriol induced regulatory T cells and protected from diabetes in NOD mice.

Silica nanoparticles: A promising platform for enhanced oral delivery of macromolecules.

Oral ingestion remains as the most convenient route of administration for the application of pharmaceuticals since it is non-invasive and does not require trained personnel to administer the drugs. Despite significant progress in novel oral drug delivery platforms over the past few decades, the oral delivery of macromolecules (particularly for peptides and proteins) is one of the major challenges faced by the biopharmaceutical industry. This is even more important since a large number of biologic drugs have been available in the past decade which typically require intravenous administration.

Regulatory T Cells Induced by Single-Peptide Liposome Immunotherapy Suppress Islet-Specific T Cell Responses to Multiple Antigens and Protect from Autoimmune Diabetes.

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4 mimotope (BDC2.5) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes.

PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions.

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy.

Non-antigen-specific stimulatory cancer immunotherapies are commonly complicated by off-target effects. Antigen-specific immunotherapy, combining viral tumor antigen or personalized neoepitopes with immune targeting, offers a solution. However, the lack of flexible systems targeting tumor antigens to cross-presenting dendritic cells (DCs) limits clinical development.

Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis.

Objective: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH.

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells.

Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux.

Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles.

Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in Kras(G12D)/p53(fl/fl) (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells.

Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.

Background: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA).

Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized.

Cosilencing of PKM-2 and MDR-1 Sensitizes Multidrug-Resistant Ovarian Cancer Cells to Paclitaxel in a Murine Model of Ovarian Cancer.

Tumor multidrug resistance (MDR) is a serious clinical challenge that significantly limits the effectiveness of cytotoxic chemotherapy. As such, complementary therapeutic strategies are being explored to prevent relapse. The altered metabolic state of cancer cells, which perform aerobic glycolysis, represents an interesting target that can enable discrimination between healthy cells and cancer cells.

Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases.

With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current therapeutic strategies. Nanoparticle-based delivery of drugs has provided means of overcoming some of these limitations by ensuring the drug payload is directed to the disease site and insuring reduced off-target activity. This review highlights the challenges posed by the solid tumor microenvironment and the systemic limitations for effective chemotherapy.

Mitochondrial biology, targets, and drug delivery.

In recent years, mitochondrial medicine has emerged as a new discipline resting at the intersection of mitochondrial biology, pathology, and pharmaceutics. The central role of mitochondria in critical cellular processes such as metabolism and apoptosis has placed mitochondria at the forefront of cell science. Advances in mitochondrial biology have revealed that these organelles continually undergo fusion and fission while functioning independently and in complex cellular networks, establishing direct membrane contacts with each other and with other organelles.

Combinatorial approach in the design of multifunctional polymeric nano-delivery systems for cancer therapy.

There have been significant advances in our understanding of cancer as a disease at the molecular level. Combined with improved diagnostic systems, the concept of personalized medicine was introduced where therapy for every patient can be customized according to their disease profile. The nanotechnology approach for formulation design and the advent of drug delivery systems for small molecules and biologics has contributed to the development of personalized medicine.

Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery.

Introduction: Cancer cells acclimatize to the harsh tumor microenvironment by altering cellular metabolism in favor of aerobic glycolysis. This process provides a source of energy and also generates essential components for macromolecular biosynthesis, which enables cellular survival. As the dependence of cancer cells on glycolysis affects tumorigenesis, it has become an attractive target for therapeutic intervention.

Macrophage-targeted delivery systems for nucleic acid therapy of inflammatory diseases.

Inflammation is an immune response that marks several pathophysiological conditions in our body. Though adaptive immune cells play a major role in the progression of the disease, components of innate immune system, mainly monocytes and macrophages play the central role in onset of inflammation. Tissue-associated macrophages are widely distributed in the body showing tremendous anatomical and functional diversity and are actively involved in maintaining the homeostasis.

Nanoemulsions in translational research-opportunities and challenges in targeted cancer therapy.

Nanoemulsion dosage form serves as a vehicle for the delivery of active pharmaceutical ingredients and has attracted great attention in drug delivery and pharmacotherapy. In particular, nanoemulsions act as an excellent vehicle for poorly aqueous soluble drugs, which are otherwise difficult to formulate in conventional dosage forms. Nanoemulsions are submicron emulsions composed of generally regarded as safe grade excipients.

Formulation development and dissolution rate enhancement of efavirenz by solid dispersion systems.

The aim of this study was to enhance the dissolution rate of efavirenz using solid dispersion systems (binary and ternary). A comparison between solvent and fusion method was also investigated. Solid dispersions of efavirenz were prepared using polyethylene glycol 8000, polyvinylpyrrolidone K30 alone and combination of both.

Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy.

PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity.

Development of solid dispersion systems of dapivirine to enhance its solubility.

Dapivirine, formerly known as TMC 120, is a poorly-water soluble anti-HIV drug, currently being developed as a vaginal microbicide. The clinical use of this drug has been limited due to its poor solubility. The aim of this study was to design solid dispersion systems of Dapivirine to improve its solubility.

Development and evaluation of PIK75 nanosuspension, a phosphatidylinositol-3-kinase inhibitor.

Purpose: PIK75 is a specific inhibitor of the p110 α isoform of phosphatidylinositol-3-kinase, an enzyme which is upregulated in several human cancers. However its poor water solubility and stability has limited its pre-clinical development.

Method: In our current work we developed and evaluated PIK75 nanosuspension prepared using high pressure homogenization technique.

Phosphatidylinositol 3-kinase inhibitor (PIK75) containing surface functionalized nanoemulsion for enhanced drug delivery, cytotoxicity and pro-apoptotic activity in ovarian cancer cells.

Purpose: Ovarian cancer is a debilitating disease, which needs multi-pronged approach of targeted drug delivery and enhanced efficacy with the use of combination therapeutics. In this study, we have examined the anticancer activity of PIK75 incorporated in surface functionalized nanoemulsions for targeted delivery to SKOV-3 cells. A pro-apoptotic molecule C(6)-ceramide was also co-delivered to augment therapeutic efficacy.

Targeting of nanoparticles in cancer: drug delivery and diagnostics.

Anticancer agents continue to be a preferred therapeutic option for several malignancies. Despite their effectiveness, oncologists are continually looking for tumor-specific anticancer agents to prevent adverse effects in patients. Targeting of imaging agents to cancerous tissue is another area that is enthusiastically explored to circumvent some of the drawbacks that current imaging agents possess, including the inability to target small tumor cells, inadequate imaging period, and the risk of renal damage.

Knowledge and reported use of antibiotics amongst immigrant ethnic groups in New Zealand.

Background: Over-use and misuse of antibiotics are major causes of antibiotic resistance. This study explored the understanding and reported use of antibiotics amongst three ethnic groups in New Zealand.

Methods: Questionnaire survey of 300 Indian, Egyptian, and Korean people.