Nanoparticles can reduce cytotoxicity, increase circulation time and increase accumulation in tumours compared to free drug. However, the value of using nanoparticles for carrying small molecules to treat tumours at the cellular level has been poorly established. Here we conducted a cytodistribution analysis on Doxorubicin-treated and Doxil-treated tumours to delineate the differences between the small molecule therapeutic Doxorubicin and its packaged liposomal formulation Doxil.
View Article and Find Full Text PDFNanoparticles need to navigate a complex microenvironment to target cells in solid tumors after extravasation. Diffusion is currently the accepted primary mechanism for nanoparticle distribution in tumors. However, the extracellular matrix can limit nanoparticle diffusion.
View Article and Find Full Text PDFThe delivery of therapeutic nanoparticles to target cells is critical to their effectiveness. Here we quantified the impact of biological barriers on the delivery of nanoparticles to macrophages in two different tissues. We compared the delivery of gold nanoparticles to macrophages in the liver versus those in the tumor.
View Article and Find Full Text PDFRho-associated kinases (ROCK) are a class of serine/threonine kinases that play important roles in various biological processes. ROCK are becoming attractive targets for drug designing. A novel scaffold was designed according to molecular hybridization strategy, then a series of 4-aryl-5-aminomethyl-thiazole-2-amines were synthesized, and their inhibitory activities on ROCK were screened by enzyme-linked immunosorbent assay (ELISA).
View Article and Find Full Text PDFThe successful delivery of nanoparticles to solid tumors depends on their ability to pass through blood vessels and into the tumor microenvironment. Here, we discovered a subset of tumor endothelial cells that facilitate nanoparticle transport into solid tumors. We named these cells nanoparticle transport endothelial cells (N-TECs).
View Article and Find Full Text PDFA series of 4-aryl-5-aminoalkyl-thiazole-2-amines were designed and synthesized, and their inhibitory activity on ROCK II was screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives had certain ROCK II inhibitory activities. Compound 10l showed ROCK II inhibitory activity with IC value of 20 nM.
View Article and Find Full Text PDFThe delivery of medical agents to a specific diseased tissue or cell is critical for diagnosing and treating patients. Nanomaterials are promising vehicles to transport agents that include drugs, contrast agents, immunotherapies and gene editors. They can be engineered to have different physical and chemical properties that influence their interactions with their biological environments and delivery destinations.
View Article and Find Full Text PDFNanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements.
View Article and Find Full Text PDFPretubulysin is a bio-precursor of highly toxic tetrapeptide tubulysins. Although pretubulysin has a much simpler chemical structure, it has similar anti-mitotic potency. A series of 2-amino-thiazole-4-carboxamides were designed and synthesized based on the structure of cemadotin.
View Article and Find Full Text PDFThere is a tremendous focus on the application of nanomaterials for the treatment of cancer. Nonprimate models are conventionally used to assess the biomedical utility of nanomaterials. However, these animals often lack an intact immunological background, and the tumors in these animals do not develop spontaneously.
View Article and Find Full Text PDFThe concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment.
View Article and Find Full Text PDFCurr Comput Aided Drug Des
August 2021
Background: Pyrazol-5-amine derivatives are an important class of heterocyclic compounds. However, there are less 4-alkyl substituted pyrazoles reported.
Objective: Here reported are the design, synthesis and biological evaluation of 3-aryl-4- alkylpyrazol-5-amines derivatives.
Lymph node follicles capture and retain antigens to induce germinal centers and long-lived humoral immunity. However, control over antigen retention has been limited. Here we discovered that antigen conjugated to nanoparticle carriers of different sizes impacts the intralymph node transport and specific cell interaction.
View Article and Find Full Text PDFTo establish a synthetic route to d3-poziotinib hydrochloride. Treatment of 4-chloro-7-hydroxyquinazolin-6-yl pivalate (1) with d3-methyliodide afforded the etherization product, which reacted with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl pivalate (3). Followed the de-protection reaction, the nucleophilic substitution (S2) reaction with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (TSP), and the de-protection reaction of t-butoxycarbonyl (Boc) group, and the amide formation reaction with acrylyl chloride, d3-poziotinib was obtained, which was converted to hydrochloride salt by treatment with concentrated hydrochloric acid (HCl).
View Article and Find Full Text PDFStudies into the interactions of serum proteins with nanoparticles are typically performed using nanoparticles that are larger than the size of proteins. Due to this size discrepancy, adsorbed proteins are commonly depicted as a globular structure surrounding a nanoparticle. Here, we asked how we should view nanoparticle-protein complexes when the nanoparticles are of similar size or smaller than the proteins with which they interact.
View Article and Find Full Text PDFUnderstanding how nanoparticles are eliminated from the body is required for their successful clinical translation. Many promising nanoparticle formulations for in vivo medical applications are large (>5.5 nm) and nonbiodegradable, so they cannot be eliminated renally.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2017
A recent metaanalysis shows that 0.7% of nanoparticles are delivered to solid tumors. This low delivery efficiency has major implications in the translation of cancer nanomedicines, as most of the nanomedicines are sequestered by nontumor cells.
View Article and Find Full Text PDFA significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver-resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role that the macrophage phenotype plays in nanoparticle uptake is unknown.
View Article and Find Full Text PDFObjectives: This field study aimed to determine the incidence and distribution of needlestick injuries among medical trainees at a community teaching hospital in Toronto, Canada.
Methods: The study was performed during the 2013-2015 academic years at Toronto East General Hospital (TEGH), a University of Toronto-affiliated community-teaching hospital during the 2013-2015 academic years. Eight-hundred and forty trainees, including medical students, residents, and post-graduate fellows, were identified and invited via email to participate in an anonymous online fluidsurveys.
Purpose: There has been limited examination of clinician scientist training in Canada, particularly regarding training integration and funding. This study assessed program structure, funding, tuition and mentorship structures available at Canadian MD/PhD programs.
Methods: Clinician Investigator Trainee Association of Canada administered an anonymous survey to current trainees and program directors that captured program structure, trainee funding, tuition and mentorship opportunities and needs across institutions.
A novel molecularly imprinted material based on silica microparticles was synthesized by surface polymerization with 3-chloro-1,2-propandiol (3-MCPD) as a template molecule. The molecularly imprinted polymer (MIP) was characterized by infrared spectroscopy and scanning electron microscopy. The adsorption of 3-MCPD by MIP was measured by gas chromatography with electron capture detection (GC-ECD) and an equilibrium binding experiment.
View Article and Find Full Text PDFThe use of tissue adhesives for internal clinical applications is limited due to a lack of materials that balance strong adhesion with biocompatibility. The use of substrate topography is explored to reduce the volume of a highly reactive and toxic glue without compromising adhesive strength. Micro-textured patches coated with a thin layer of cyanoacrylate glue achieve similar adhesion levels to patches employing large amounts of adhesive, and is superior to the level of adhesion achieved when a thin coating is applied to a non-textured patch.
View Article and Find Full Text PDF