46 research outputs found
Secretory phospholipase A<sub>2</sub> responsive liposomes exhibit a potent anti-neoplastic effect in vitro, but induce unforeseen severe toxicity in vivo
The Possible "Proton Sponge " Effect of Polyethylenimine (PEI) Does Not Include Change in Lysosomal pH.
Polycations such as polyethylenimine (PEI) are used in many novel nonviral vector designs and there are continuous efforts to increase our mechanistic understanding of their interactions with cells. Even so, the mechanism of polyplex escape from the endosomal/lysosomal pathway after internalization is still elusive. The “proton sponge ” hypothesis remains the most generally accepted mechanism, although it is heavily debated. This hypothesis is associated with the large buffering capacity of PEI and other polycations, which has been interpreted to cause an increase in lysosomal pH even though no conclusive proof has been provided. In the present study, we have used a nanoparticle pH sensor that was developed for pH measurements in the endosomal/lysosomal pathway. We have carried out quantitative measurements of lysosomal pH as a function of PEI content and correlate the results to the “proton sponge ” hypothesis. Our measurements show that PEI does not induce change in lysosomal pH as previously suggested and quantification of PEI concentrations in lysosomes makes it uncertain that the “proton sponge ” effect is the dominant mechanism of polyplex escape
Ligand-Induced Tyrosine Phosphorylation of Cysteinyl Leukotriene Receptor 1 Triggers Internalization and Signaling in Intestinal Epithelial Cells
Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer
Live-cell fluorescent microscopy platforms for real-time monitoring of polyplex-cell interaction: Basic guidelines
Heavy Chain Only Antibodies: A New Paradigm in Personalized HER2+ Breast Cancer Therapy
Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen-binding fragments in cancer targeting and therapy. VHHs express low immunogenicity, are highly robust and easy to manufacture and have the ability to recognize hidden or uncommon epitopes. We highlight the utility of VHH in design of new molecular, multifunctional particulate and immune cell-based systems for combating HER2+ breast cancer
Differential Modulation of Cellular Bioenergetics by Poly(<sub>L</sub> -lysine)s of Different Molecular Weights
Adenosine inhibits human astrocyte proliferation independently of adenosine receptor activation
Protein Transduction Domain Mimics Facilitate Rapid Antigen Delivery into Monocytes
Delivering
peptides and proteins with intracellular function represents
a promising avenue for therapeutics, but remains a challenge due to
the selective permeability of the plasma membrane. The successful
delivery of cytosolically active proteins would enable many opportunities,
including improved vaccine development through major histocompatibility
complex (MHC) class I antigen display. Extended research using cell-penetrating
peptides (CPPs) has aimed to facilitate intracellular delivery of
exogenous proteins with some success. A new class of polymer-based
mimics termed protein transduction domain mimics (PTDMs), which maintain
the positive charge and amphiphilic nature displayed by many CPPs,
was developed using a poly-norbornene-based backbone. Herein, we use
a previously characterized PTDM to investigate delivery of the model
antigen SIINFEKL into leukocytes. Peptide delivery into over 90% of
CD14+ monocytes was detected in less than 15 min with nominal inflammatory
cytokine response and high cell viability. The co-delivery of a TLR9
agonist and antigen using the PTDM into antigen-presenting cells in
vitro showed presentation of SIINFEKL in association with MHC class
I molecules, in addition to upregulation of classical differentiation
markers revealing the ability of the PTDM to successfully deliver
cargo intracellularly and show application in the field of immunotherapy