Glucan Particles for Macrophage Targeted Delivery of Nanoparticles

Glucan particles (GPs) are hollow, porous 2–4 μm microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The 1,3-β-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. GPs have been used for macrophage-targeted delivery of soluble payloads (DNA, siRNA, protein, and small molecules) encapsulated inside the hollow GPs via core polyplex and layer-by-layer (LbL) synthetic strategies. In this communication, we report the incorporation of nanoparticles as cores inside GPs (GP-NP) or electrostatically bound to the surface of chemically derivatized GPs (NP-GP). GP nanoparticle formulations benefit from the drug encapsulation properties of NPs and the macrophage-targeting properties of GPs. GP nanoparticle formulations were synthesized using fluorescent anionic polystyrene nanoparticles allowing visualization and quantitation of NP binding and encapsulation. Mesoporous silica nanoparticles (MSNs) containing the chemotherapeutic doxorubicin (Dox) were bound to cationic GPs. Dox-MSN-GPs efficiently delivered Dox into GP phagocytic cells resulting in enhanced Dox-mediated growth arrest

Myelin, cPLA2, and Azithromycin: Modulation of Macrophage Activation in Spinal Cord Injury Inflammation

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory responses are promising therapeutic targets; however, there are very few therapeutic options to treat SCI and none that target macrophages. Here, we provide evidence that treatment with the immunomodulatory antibiotic azithromycin (AZM), initiated after SCI, improves recovery by targeting macrophage activation. There is an urgent need for the development of new therapies for the treatment of SCI. Macrophage-targeted therapies hold great promise; however, these treatment candidates require additional development before they can advance towards clinical use. Here we discuss the continued development of cPLA2 as a therapeutic target, the steps necessary to advance AZM towards clinical use, and lastly, we review additional macrophage-targeted therapies currently in development. Collectively this body of work identifies key mechanisms driving macrophage pathophysiology after SCI and identifies macrophage-targeted therapies that reduce this neuroinflammation to improve recovery after SCI

ペプチド及びタンパク質搭載細胞外小胞を利用したマクロファージを標的とする疾患治療法の開発

京都大学新制・課程博士博士(薬科学)甲第24549号薬科博第166号新制||薬科||18(附属図書館)京都大学大学院薬学研究科薬科学専攻(主査)教授 髙倉 喜信, 教授 山下 富義, 教授 小野 正博学位規則第4条第1項該当Doctor of Pharmaceutical SciencesKyoto UniversityDFA

Macrophage-targeted PET imaging of Rheumatoid Arthritis: opportunities for early diagnostics and therapy monitoring

Voskuijl, A.E. [Promotor]Hoekstra, O.S. [Promotor]Laken, C.J. van der [Copromotor

A Novel Lactic Acid Bacteria Mixture: Macrophage-Targeted Prophylactic Intervention in Colorectal Cancer Management

Colorectal cancer (CRC) is one of the most common forms of cancer. Its onset from chronic inflammation is widely accepted. Moreover, dysbiosis plays an undeniable role, thus the use of probiotics in CRC has been suggested. They exhibit both anti- and pro-inflammatory properties and restore balance in the microbiota. The aim of this study was to investigate the immunomodulatory properties of six lactobacilli with probiotic features in an in vitro model of macrophage-like cells and to test these pooled probiotics for their anti-tumour properties in a chemically induced CRC model using Wistar male rats. Upon co-culture of M1- and M2-like macrophages with lactobacilli, cytokine release (TNF-α, IL-1β, IL-18, IL-23) and phagocytic activity using fluorescent-labelled bacteria were tested. The effects of orally administered probiotics on basic cancer and immune parameters and cytokine concentration (TNF-α, IL-1β, IL-18) in colon tumours were studied. Tested lactobacilli exhibited both pro- and anti-inflammatory properties in in vitro conditions. In vivo study showed that the administration of probiotics was able to decrease multiplicity, volume and total tumour numbers, restore colon length (p &lt; 0.05) and increase IL-18 production (p &lt; 0.05) in tumour tissue. These data indicate both an immunomodulatory effect of probiotics on distinct macrophage subsets and a protective effect against chemically-induced CRC.</jats:p

Crossing Biological Barriers for Leishmaniasis Therapy: From Nanomedicinal Targeting Perspective

Despite past 60 years of extensive research in antileishmanial drug development, the successful therapy of this disease cannot be achieved at full potential. The biological barriers encountered by the therapeutic modalities favor the disseminations of the disease like intramacrophage location of parasite, lack of oral bioavailability, permeability across the cutaneous tissue, and active efflux of the drug. Nanomedicines are specifically engineered nano-sized delivery systems. The goal of designing a nanomedicine is to achieve the specific therapeutic objective via targeting the specific cells and intracellular locations, pharmacological receptors, enzymes and proteins, crossing biological barriers, and navigation through endocytic pathways. This chapter will cover various nanomedicinal approaches like targeting the macrophages, pathological organs, efflux pumps, metabolic enzymes, redox biology of Leishmania by using polymeric and metal nanocarriers to overcome all the biological barriers thus providing a successful alternative over the conventional therapies

Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc

Inhalable Formulation Based on Lipid-Polymer Hybrid Nanoparticles for the Macrophage Targeted Delivery of Roflumilast

Here, novel lipid-polymer hybrid nanoparticles (LPHNPs), targeted to lung macrophages, were realized as potential carriers for Roflumilast administration in the management of chronic obstructive pulmonary disease (COPD). To achieve this, Roflumilast-loaded fluorescent polymeric nanoparticles, based on a polyaspartamide-polycaprolactone graft copolymer, and lipid vesicles, made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-phosphoethanolamine-N-(polyethylene glycol)-mannose, were properly combined using a two-step method, successfully obtaining Roflumilast-loaded hybrid fluorescent nanoparticles (Man-LPHFNPs@Roflumilast). These exhibit colloidal size and a negative ζ potential, 50 wt % phospholipids, and a core-shell-type morphology; they slowly release the entrapped drug in a simulated physiological fluid. The surface analysis also demonstrated their high surface PEG density, which confers mucus-penetrating properties. Man-LPHFNPs@Roflumilast show high cytocompatibility toward human bronchial epithelium cells and macrophages and are uptaken by the latter through an active mannose-mediated targeting process. To achieve an inhalable formulation, the nano-into-micro strategy was applied, encapsulating Man-LPHFNPs@Roflumilast in poly(vinyl alcohol)/leucine-based microparticles by spray-drying

Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis

Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients