Micelle-like nanoparticles as siRNA and miRNA carriers for cancer therapy.

Gene therapy has emerged as an alternative in the treatment of cancer, particularly in cases of resistance to chemo and radiotherapy. Different approaches to deliver genetic material to tumor tissues have been proposed, including the use of small non-coding RNAs due to their multiple mechanisms of action. However, such promise has shown limits in in vivo application related to RNA's biological instability and stimulation of immunity, urging the development of systems able to overcome those barriers.

Effect of photo-degradation on the structure, stability, aggregation, and function of an IgG1 monoclonal antibody.

Photostability testing of therapeutic proteins is a critical requirement in the development of biologics. Upon exposure to light, pharmaceutical proteins may undergo a change in structure, stability, and functional properties that could have a potential impact on safety and efficacy. In this work, we studied how exposure to light, according to ICH guidelines, leads to photo-oxidation of a therapeutic IgG1 mAb.

Optimizing liposomes for delivery of Bowman-Birk protease inhibitors - Platforms for multiple biomedical applications.

One of the major challenges in the administration of therapeutic proteins involves delivery limitations. Liposomes are well-known drug delivery systems (DDS) that have been used to overcome this drawback; nevertheless, low protein entrapment efficiency (EE) still limits their wide biomedical application on a commercial scale. In the present work, different methods for protein entrapment into liposomes were tested in order to obtain tailored DDS platforms for multiple biomedical applications.

Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents.

Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties in vitro.

Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins.

Purpose: To determine the role of hepatic radiofrequency ablation (RFA) heating parameters and their activation of heat shock proteins (HSPs) in modulating distant tumor growth.

Methods And Materials: First, to study the effects of RFA dose on distant tumor growth, rats with subcutaneous R3230 adenocarcinoma (10 ± 1 mm) were assigned to 3 different hepatic RF doses (60 °C × 10 min, 70 °C × 5 min or 90 °C × 2 min) that induced identical sized ablation or sham (n = 6/arm). Post-RFA tumor growth rates, cellular proliferation (Ki-67) and microvascular density (MVD) were compared at 7d.

Biophysical Properties and Heating-Induced Aggregation of Lysine-Conjugated Antibody-Drug Conjugates.

The commercially available antibody-drug conjugate (ADC) product, Kadcyla is synthesized using a 2-step reaction, wherein the linker is conjugated to native lysines on the mAb in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine-conjugated ADC (Syn-ADC) on the same trastuzumab scaffold as Kadcyla using a 1-step reaction. Mass spectrometry of both products revealed a subpopulation of Kadcyla containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the 1-step reaction ADC product.

Transferrin-targeted, resveratrol-loaded liposomes for the treatment of glioblastoma.

Glioblastomas (GBMs) are highly aggressive brain tumors with a very grim prognosis even after multi-modal therapeutic regimens. Conventional chemotherapeutic agents frequently lead to drug resistance and result in severe toxicities to non-cancerous tissues. Resveratrol (RES), a natural polyphenol with pleiotropic health benefits, has proven chemopreventive effects in all the stages of cancer including initiation, promotion and progression.

Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer.

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular.

Flow Microscopy Imaging Is Sensitive to Characteristics of Subvisible Particles in Peginesatide Formulations Associated With Severe Adverse Reactions.

The presence of subvisible particles in formulations of therapeutic proteins is a risk factor for adverse immune responses. Although the immunogenic potential of particulate contaminants likely depends on particle structural characteristics (e.g.

Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK).

Enoyl-acyl carrier protein (ACP) reductase II (FabK) is a critical rate-limiting enzyme in the bacterial type II fatty-acid synthesis (FAS II) pathway. FAS II pathway enzymes are markedly disparate from their mammalian analogs in the FAS I pathway in both structure and mechanism. Enzymes involved in bacterial fatty-acid synthesis represent viable drug targets for Gram-negative pathogens, and historical precedent exists for targeting them in the treatment of diseases of the oral cavity.

Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer.

Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using and experiments.

Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG.

Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors.

Effect of Polysorbate 20 and Polysorbate 80 on the Higher-Order Structure of a Monoclonal Antibody and Its Fab and Fc Fragments Probed Using 2D Nuclear Magnetic Resonance Spectroscopy.

We examined how polysorbate 20 (PS20; Tween 20) and polysorbate 80 (PS80; Tween 80) affect the higher-order structure of a monoclonal antibody (mAb) and its antigen-binding (Fab) and crystallizable (Fc) fragments, using near-UV circular dichroism and 2D nuclear magnetic resonance (NMR). Both polysorbates bind to the mAb with submillimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure.

Dendrimers as Nanocarriers for Nucleic Acid and Drug Delivery in Cancer Therapy.

Dendrimers are highly branched polymers with easily modifiable surfaces. This makes them promising structures for functionalization and also for conjugation with drugs and DNA/RNA. Their architecture, which can be controlled by different synthesis processes, allows the control of characteristics such as shape, size, charge, and solubility.

d-α-Tocopheryl Succinate/Phosphatidyl Ethanolamine Conjugated Amphiphilic Polymer-Based Nanomicellar System for the Efficient Delivery of Curcumin and To Overcome Multiple Drug Resistance in Cancer.

Nanomedicines have emerged as a promising treatment strategy for cancer. Multiple drug resistance due to overexpression of various drug efflux transporters and upregulation of apoptotic inhibitory pathways in cancer cells are major barriers that limit the success of chemotherapy. Here, we developed a d-α-tocopherol (α-TOS)/lipid-based copolymeric nanomicellar system (VPM) by conjugating phosphatidyl ethanolamine (PE) and α-TOS with poly(ethylene glycol) (PEG) via an amino acid linkage.

PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.

Unlabelled: A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements.

Applications of label-free, quantitative phase holographic imaging cytometry to the development of multi-specific nanoscale pharmaceutical formulations.

A label-free, high content, time-lapse holographic imaging system was applied to studies in pharmaceutical compound development. Multiple fields of cellular images are obtained over typically several day evaluations within standard CO incubators. Events are segmented to obtain population data of cellular features, which are displayed in scattergrams and histograms.

The Cytotoxic Action of Cytochrome C/Cardiolipin Nanocomplex (Cyt-CL) on Cancer Cells in Culture.

Purpose: The effect of existing anti-cancer therapies is based mainly on the stimulation of apoptosis in cancer cells. Here, we have demonstrated the ability of a catalytically-reactive nanoparticle-based complex of cytochrome c with cardiolipin (Cyt-CL) to induce the apoptosis and killing of cancer cells in a monolayer cell culture.

Methods: Cyt-CL nanoparticles were prepared by complexing CytC with different molar excesses of CL.

Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been known as a promising agent for cancer therapy due to its specific apoptosis-inducing effect on tumor cells rather than most normal cells. However, systemically delivered TRAIL suffers from a rapid clearance from the body with an extremely short half-life. Thermally responsive elastin-like polypeptides (ELPs) are a promising class of temperature sensitive biopolymers based on the structural motif found in mammalian tropoelastin and retain the advantages of polymeric drug delivery systems.

Immunogenicity of Structurally Perturbed Hen Egg Lysozyme Adsorbed to Silicone Oil Microdroplets in Wild-Type and Transgenic Mouse Models.

Silicone oil microdroplets may act as adjuvants, promoting unwanted immune responses against both foreign and self-proteins. Proteins often unfold upon adsorption to silicone oil microdroplets, but it is unclear how such unfolding might affect the immune response. In this study, we found that hen egg lysozyme (HEL) readily adsorbed to silicone oil microdroplets and perturbed the conformation of HEL.

Microflow Imaging Analyses Reflect Mechanisms of Aggregate Formation: Comparing Protein Particle Data Sets Using the Kullback-Leibler Divergence.

Subvisible particles in therapeutic protein formulations are an increasing manufacturing and regulatory concern because of their potential to cause adverse immune responses. Flow imaging microscopy is used extensively to detect subvisible particles and investigate product deviations, typically by comparing imaging data using histograms of particle descriptors. Such an approach discards much information and requires effort to interpret differences, which is problematic when comparing many data sets.

Multifunctional Liposomes.

Liposomes have come a long way since their conception in the 1960s, when they were envisioned primarily for drug delivery. Besides serving the important function of the delivery of a variety of drugs, liposomes offer a platform for the co-delivery of a range of therapeutic and diagnostic agents with different physicochemical properties. They are also amenable to the addition of various targeting moieties such as proteins, sugars, and antibodies for selective targeting at a desired site, including tumors.

Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development.

Every major biopharmaceutical company incorporates a protein crystallography unit that is central to its structure-based drug discovery efforts. Yet these capabilities are rarely leveraged toward the formal higher order structural characterization that is so challenging but integral to large-scale biologics manufacturing. Although the biotech industry laments the shortcomings of its favored biophysical techniques, x-ray crystallography is not even considered for drug development.

Gadolinium-Loaded Polychelating Polymer-Containing Tumor-Targeted Liposomes.

Magnetic resonance (MR) is one of the most widely used imaging modalities in contemporary medicine to obtain images of pathological areas. Still, there is a big effort to facilitate the accumulation of contrast in the required zone and further increase a local spatial concentration of a contrast agent for better imaging. Certain particulate carriers able to carry multiple contrast moieties can be used for an efficient delivery of contrast agents to areas of interest and enhancing a signal from these areas.