Folate Targeting Peptide Conjugates for Inflammatory Response Suppression.

Background And Objective: Protein kinases known as mitogen-activated protein kinases (MAPKs) are responsible for regulating a wide variety of physiological cell responses by generating and release of inflammatory mediators. Suppressing these inflammatory mediators can be utilized to control the propagation of inflammation. During the course of this research, we created folate-targeted MK2 inhibitor conjugates and analyzed the antiinflammatory effects of these compounds.

In Vitro Electrochemical Detection of Hydrogen Peroxide in Activated Macrophages via a Platinum Microelectrode Array.

Oxidative stress, an excess of endogenous or exogenous reactive oxygen species (ROS) in the human body, is closely aligned with inflammatory responses. ROS such as hydrogen peroxide (HO), superoxide, and radical hydroxyl ions serve essential functions in fighting infection; however, chronic elevation of these species irreversibly damages cellular components. Given the central role of inflammation in a variety of diseases, including Alzheimer's disease and rheumatoid arthritis, a low-cost, extracellular, non-invasive assay of HO measurement is needed.

Efficient LRP1-Mediated Uptake and Low Cytotoxicity of Peptide L57 In Vitro Shows Its Promise as CNS Drug Delivery Vector.

Although an abundance of drug candidates exists which are aimed at the remediation of central nervous system (CNS) disorders, the utility of some are severely limited by their inability to cross the blood brain barrier. Potential drug delivery systems such as the Angiopep family of peptides have shown modest potential; however, there is a need for novel drug delivery candidates that incorporate peptidomimetics to enhance the efficiency of transcytosis, specificity, and biocompatibility. Here, we report on the first in vitro cellular uptake and cytotoxicity study of a peptidomimetic, cationic peptide, L57.

Selective liposome targeting of folate receptor positive immune cells in inflammatory diseases.

Activated macrophages play a key role in the development and maintenance of inflammatory diseases such as atherosclerosis, lupus, psoriasis, rheumatoid arthritis, ulcerative colitis, and many others. These activated macrophages, but not resting or quiescent macrophages highly up-regulate folate receptor beta (FR-β). This differential expression of FR-β provides a mechanism to selectively deliver imaging and therapeutic agents utilizing folate as a targeting molecule.

Folate-conjugated liposomes target and deliver therapeutics to immune cells in a rat model of rheumatoid arthritis.

Aim: We endeavored to create a folate-targeted liposome (Fol-liposome) that could selectively target areas of inflammation.

Materials & Methods: Fol-liposomes were prepared with encapsulated DiD fluorophore or betamethasone (BM) to image and treat an adjuvant-induced rat model of rheumatoid arthritis.

Results: Fol-liposomes selectively accumulated in arthritic rat paws to a greater extent than nontargeted liposomes.

Folate-Targeted Dendrimers Selectively Accumulate at Sites of Inflammation in Mouse Models of Ulcerative Colitis and Atherosclerosis.

Folate-receptor-positive activated macrophages are critical for the development and maintenance of many chronic inflammatory and autoimmune diseases. Previously, small-molecule folate-targeted conjugates were found to specifically bind to these activated macrophages in vitro and selectively accumulate at sites of inflammation in vivo. While these small-molecule conjugates have shown promise, the use of a folate-targeted, higher cargo capacity nanovehicle may prove superior in delivering imaging or therapeutic agents in vivo.

Delivery of anti-inflammatory peptides from hollow PEGylated poly(NIPAM) nanoparticles reduces inflammation in an ex vivo osteoarthritis model.

Targeted delivery of anti-inflammatory osteoarthritis treatments have the potential to significantly decrease undesirable systemic side effects and reduce required therapeutic dosage. Here we present a targeted, non-invasive drug delivery system to decrease inflammation in an osteoarthritis model. Hollow thermoresponsive poly(N-isopropylacrylamide) (pNIPAM) nanoparticles have been synthesized via degradation of a N,N'-bis(acryloyl)cystamine (BAC) cross-linked core out of a non-degradable pNIPAM shell.

Controlled release of anti-inflammatory peptides from reducible thermosensitive nanoparticles suppresses cartilage inflammation.

Characterized by pain, cartilage degradation, and inflammation, osteoarthritis is often treated with anti-inflammatory therapies that provide short-term relief but can have adverse side effects; intra-articular drug delivery systems with controlled release of anti-inflammatory peptides using degradable poly(N-isopropylacrylamide) (pNIPAM) nanoparticles could prolong relief and minimize these side effects. Nanoparticles provide a biocompatible drug carrier that can protect encapsulated therapeutics from enzymatic degradation and increase payload delivery upon encountering a degradation stimulus. Here we demonstrate passive targeting of inflamed cartilage ex vivo by uptake of PEGylated pNIPAM nanoparticles with degradable disulfide crosslinks (abbreviated as NGPEGSS) into chondrocytes and subsequent intracellular release of an anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK).

Comparison of nanoparticle penetration into solid tumors and sites of inflammation: studies using targeted and nontargeted liposomes.

Aim: The vast majority of nanomedicine research is focused on the use of nanoparticles for the diagnosis and treatment of cancer. However, the dense extracellular matrix of solid tumors restricts nanoparticle penetration, raising the question of whether the best applications of nanomedicines lie in oncology.

Materials & Methods: In this study, the uptake of folate-conjugated liposomes was compared between folate receptor-expressing tumors and folate receptor+ inflammatory lesions within the same mouse.

Release of anti-inflammatory peptides from thermosensitive nanoparticles with degradable cross-links suppresses pro-inflammatory cytokine production.

Pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) are mediators in the development of many inflammatory diseases. To demonstrate that macrophages take up and respond to thermosensitive nanoparticle drug carriers, we synthesized PEGylated poly(N-isopropylacrylamide-2-acrylamido-2-methyl-1-propanesulfonate) particles cross-linked with degradable disulfide (N,N'-bis(acryloyl)cystamine) (NGPEGSS). An anti-inflammatory peptide (KAFAK) was loaded and released from the thermosensitive nanoparticles and shown to suppress levels of TNF-α and IL-6 production in macrophages.

Development of tumor-targeted near infrared probes for fluorescence guided surgery.

Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions.

A folate receptor-α-specific ligand that targets cancer tissue and not sites of inflammation.

Unlabelled: Folic acid has been frequently exploited to target attached drugs to cells that overexpress a folate receptor (FR). Unfortunately, folic acid and folate-linked drugs bind equally well to both major isoforms of the FR-that is, FR-α, which is primarily expressed on malignant cells, and FR-β, which is upregulated on activated monocytes and macrophages. Because both major isoforms of FR can be expressed simultaneously in the same organism, folic acid cannot enable selective targeting of therapeutic and imaging agents to either tumor masses or sites of inflammation.