JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
A nano-enabled cancer-specific ITCH RNAi chemotherapy booster for pancreatic cancer.
Nanomedicine
PUBLISHED: 05-15-2014
Show Abstract
Hide Abstract
Gemcitabine is currently the standard therapy for pancreatic cancer. However, growing concerns over gemcitabine resistance mean that new combinatory therapies are required to prevent loss of efficacy with prolonged treatment. Here, we suggest that this could be achieved through co-administration of RNA interference agents targeting the ubiquitin ligase ITCH. Stable anti-ITCH siRNA and shRNA dendriplexes with a desirable safety profile were prepared using generation 3 poly(propylenimine) dendrimers (DAB-Am16). The complexes were efficiently taken up by human pancreatic cancer cells and produced a 40-60% decrease in ITCH RNA and protein expression in vitro (si/shRNA) and in a xenograft model of pancreatic cancer (shRNA). When co-administered with gemcitabine (100mg/kg/week) at a subtherapeutic dose, treatment with ITCH-shRNA (3x 50mg/week) was able to fully suppress tumour growth for 17days, suggesting that downregulation of ITCH mediated by DAB-Am16/shRNA sensitizes pancreatic cancer to gemcitabine in an efficient and specific manner.
Related JoVE Video
Strategies to deliver peptide drugs to the brain.
Mol. Pharm.
PUBLISHED: 03-21-2014
Show Abstract
Hide Abstract
Neurological diseases such as neurodegeneration, pain, psychiatric disorders, stroke, and brain cancers would greatly benefit from the use of highly potent and specific peptide pharmaceuticals. Peptides are especially desirable because of their low inherent toxicity. The presence of the blood brain barrier (BBB), their short duration of action, and their need for parenteral administration limits their clinical use. However, over the past decade there have been significant advances in delivering peptides to the central nervous system. Angiopep peptides developed by Angiochem (Montreal, Canada), transferrin antibodies developed by ArmaGen (Santa Monica, USA), and cell penetrating peptides have all shown promise in delivering therapeutic peptides across the BBB after intravenous administration. Noninvasive methods of delivering peptides to the brain include the use of chitosan amphiphile nanoparticles for oral delivery and nose to brain strategies. The uptake of the chitosan amphiphile nanoparticles by the gastrointestinal epithelium is important for oral peptide delivery. Finally protecting peptides from plasma degradation is integral to the success of most of these peptide delivery strategies.
Related JoVE Video
Physical characterisation and long-term stability studies on quaternary ammonium palmitoyl glycol chitosan (GCPQ)--a new drug delivery polymer.
J Pharm Sci
PUBLISHED: 02-03-2014
Show Abstract
Hide Abstract
N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) is a self-assembling polymer, which enables the oral bioavailability of peptide and hydrophobic drugs. In preparation for clinical testing, here we examine GCPQ's synthesis reproducibility, pKa, thermal, and rheological properties. GCPQ was synthesised by acid degradation of glycol chitosan (GC), reaction with palmitic acid N-hydroxysuccinimide (PNS) and methylation. A GC monomer, PNS molar feed ratio of 0.92 together with a gravimetric feed ratio for N-palmitoyl-6-O-glycolchitosan, methyl iodide of 3.3, reproducibly produces GCPQ48 (Mw = 19.9 ± 9.9 kDa, Mn = 13.1 ± 2.4 kDa, mol % palmitoylation = 23 ± 2.7, mol % quaternisation = 10 ± 0.23, n = 56). GCPQ48 decomposes at 218 ± 4.3 °C, is glassy at room temperature (Tg = 164.4 ± 8.5 °C), is a weak base (pKa = 5.99 ± 0.15), and produces micellar dispersions at neutral pH. Below a concentration of 0.07 g mL(-1) , GCPQ48 dispersions showed Newtonian rheological behaviour but at higher concentrations, the polymer undergoes shear thinning because of the chain disentanglement at high shear rates. GCPQ48 forms a network of micelles and concentrated (0.09 g mL(-1) ) dispersions are viscoelastic, with the storage modulus exceeding the loss modulus at high frequencies. Solid GCPQ48 was stable when stored at room temperature for 18 months.
Related JoVE Video
Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.
Sci Rep
PUBLISHED: 06-03-2013
Show Abstract
Hide Abstract
The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression.
Related JoVE Video
GC-targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models.
J. Med. Chem.
PUBLISHED: 03-21-2013
Show Abstract
Hide Abstract
DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-?B with its cognate DNA binding sequence.
Related JoVE Video
Dextran-pegylated microparticles for enhanced cellular uptake of hydrophobic drugs.
Eur J Pharm Biopharm
PUBLISHED: 01-21-2013
Show Abstract
Hide Abstract
Polyethylene glycol monosubstituted with a polymerizable acrylic moiety was linked to 6-carboxy free position on dextran side chains and then subjected to radical polymerization with a comonomer in order to obtain microspheres for the oral controlled release of ketoconazole, a hydrophobic model drug. Microparticles were submitted to studies on their ability to absorb and retain water. Cell uptake studies, in the presence and absence of mucus, across two different monolayers, respectively, HT29-MTX-E12 and Caco-2, were done. Cytotoxicity studies were carried out to calculate the IC?? value. The ability of microspheres to open monolayers tight junctions was tested by measuring their TEER values. Images of cell uptake were visualized by CLSM. In HT29-MTX-E12 cells, more mucoadhesion and drug internalization is seen thanks to the presence of PEG and dextran chains.
Related JoVE Video
Functional characterization of heat shock protein 90 targeted compounds.
Anal. Biochem.
PUBLISHED: 01-20-2013
Show Abstract
Hide Abstract
Heat shock protein 90 (Hsp90) is an attractive cancer target that possesses two potential binding domains at the C and N termini. Nevertheless, assays that can reliably distinguish between the C- and N-terminal Hsp90 inhibitors and quantitatively characterize candidate drugs are limited. Here we report an Hsp90 binding assay and ATPase inhibition assay that can not only separate the C- and N-terminal inhibitors but also quantitatively determine their respective IC50 values.
Related JoVE Video
Nanofiber-based delivery of therapeutic peptides to the brain.
ACS Nano
PUBLISHED: 01-10-2013
Show Abstract
Hide Abstract
The delivery of therapeutic peptides and proteins to the central nervous system is the biggest challenge when developing effective neuropharmaceuticals. The central issue is that the blood-brain barrier is impermeable to most molecules. Here we demonstrate the concept of employing an amphiphilic derivative of a peptide to deliver the peptide into the brain. The key to success is that the amphiphilic peptide should by design self-assemble into nanofibers wherein the active peptide epitope is tightly wrapped around the nanofiber core. The nanofiber form appears to protect the amphiphilic peptide from degradation while in the plasma, and the amphiphilic nature of the peptide promotes its transport across the blood-brain barrier. Therapeutic brain levels of the amphiphilic peptide are achieved with this strategy, compared with the absence of detectable peptide in the brain and the consequent lack of a therapeutic response when the underivatized peptide is administered.
Related JoVE Video
Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles.
Mol. Pharm.
PUBLISHED: 11-29-2011
Show Abstract
Hide Abstract
As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.
Related JoVE Video
High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity.
Chem. Commun. (Camb.)
PUBLISHED: 08-24-2011
Show Abstract
Hide Abstract
Glycosylated analogues of novobiocin, discovered using a broad library of enzymes, have 100-fold improved activity against breast, brain, pancreatic, lung and ovarian cancers and ablated associated off-target activity leading to an up to 2.7 × 10(4) fold increase in selectivity.
Related JoVE Video
Targeting pancreatic cancer with a G-quadruplex ligand.
Bioorg. Med. Chem.
PUBLISHED: 08-16-2011
Show Abstract
Hide Abstract
The integrity of telomeres in most cancer cells is maintained by the action of the telomerase enzyme complex, which catalyzes the synthesis of telomeric DNA repeats in order to replace those lost during replication. Telomerase is especially up-regulated in metastatic cancer and is thus emerging as a major therapeutic target. One approach to telomerase inhibition involves the sequestration of the single-stranded 3 ends of telomeric DNA into higher-order quadruplex structures. We have recently shown that tetra-substituted naphthalene diimide compounds are potent quadruplex-stabilizing molecules with telomerase inhibitory activity in cells. We show here that one such compound, BMSG-SH-3, which has been optimized by computer modeling, has significant in vivo antitumor activity against a model for pancreatic cancer, a cancer that is especially resistant to current therapies. A large reduction in telomerase activity in treated tumors was observed and the naphthalene diimide compound was found to be selectively localized in the treated tumors. We find that the expression of the therapeutically important chaperone protein HSP90, a regulator of telomerase is also reduced in vivo by BMSG-SH-3 treatment. The compound is a potent stabilizer of two G-quadruplex sequences found in the promoter region of the HSP90 gene, as well as a G-quadruplex from human telomeric DNA. It is proposed that the simultaneous targeting of these quadruplexes may be an effective anti-tumor strategy.
Related JoVE Video
Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo.
J Pharm Sci
PUBLISHED: 09-17-2010
Show Abstract
Hide Abstract
Cationic polyamines such as the poly(propylenimine) dendrimers (DAB16) are anti-tumour agents (Dufes et al., 2005, Cancer Res 65:8079-8084). Their mechanism of action is poorly understood, but the lack of in vivo toxicity suggests cancer specificity. To explore this polyamine pharmacophore we cross-linked the aza-cyclic compound, hexacyclen, with 1,4-dibromobutane or 1,8-dibromooctane to yield the polyamines [poly(butylhexacyclen)--CL4] or [poly(octylhexacyclen)--CL8] respectively, both free of primary amines. We characterised the compounds and their respective nanoparticles and examined their interaction with the putative targets of the cationic polyamines: the cell membrane and DNA. Like DAB 16, CL4 and CL8 bind plasmid DNA and all three compounds interrupted the cell cycle of A431 epidermoid carcinoma cells in the S-phase. Additionally all three compounds disrupted erythrocyte membranes, with CL8 and DAB 16 being more active, in this respect, than CL4. CL4 (IC(50)?=775.1?µg?mL(-1)) and CL8 (IC(50)?=8.4?µg?mL(-1)), in a similar manner to DAB 16, were anti-proliferative against A431 cells; although unlike DAB 16, CL4 and CL8 were not tumouricidal against A431 xenografts in mice, indicating that primary amines may play an important role in the in vivo activity of DAB 16.
Related JoVE Video
In silico modelling of drug-polymer interactions for pharmaceutical formulations.
J R Soc Interface
PUBLISHED: 06-02-2010
Show Abstract
Hide Abstract
Selecting polymers for drug encapsulation in pharmaceutical formulations is usually made after extensive trial and error experiments. To speed up excipient choice procedures, we have explored coarse-grained computer simulations (dissipative particle dynamics (DPD) and coarse-grained molecular dynamics using the MARTINI force field) of polymer-drug interactions to study the encapsulation of prednisolone (log p = 1.6), paracetamol (log p = 0.3) and isoniazid (log p = -1.1) in poly(L-lactic acid) (PLA) controlled release microspheres, as well as the encapsulation of propofol (log p = 4.1) in bioavailability enhancing quaternary ammonium palmitoyl glycol chitosan (GCPQ) micelles. Simulations have been compared with experimental data. DPD simulations, in good correlation with experimental data, correctly revealed that hydrophobic drugs (prednisolone and paracetamol) could be encapsulated within PLA microspheres and predicted the experimentally observed paracetamol encapsulation levels (5-8% of the initial drug level) in 50 mg ml(-1) PLA microspheres, but only when initial paracetamol levels exceeded 5 mg ml(-1). However, the mesoscale technique was unable to model the hydrophilic drug (isoniazid) encapsulation (4-9% of the initial drug level) which was observed in experiments. Molecular dynamics simulations using the MARTINI force field indicated that the self-assembly of GCPQ is rapid, with propofol residing at the interface between micellar hydrophobic and hydrophilic groups, and that there is a heterogeneous distribution of propofol within the GCPQ micelle population. GCPQ-propofol experiments also revealed a population of relatively empty and drug-filled GCPQ particles.
Related JoVE Video
Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer.
Int. J. Oncol.
PUBLISHED: 05-09-2009
Show Abstract
Hide Abstract
Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m(2) doxorubicin-equivalent) were given i.v., together with 123I-labelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.
Related JoVE Video
Cancer-specific transgene expression mediated by systemic injection of nanoparticles.
Cancer Res.
PUBLISHED: 03-03-2009
Show Abstract
Hide Abstract
The lack of safe and efficient systemic gene delivery vectors has largely reduced the potential of gene therapy in the clinic. Previously, we have reported that polypropylenimine dendrimer PPIG3/DNA nanoparticles are capable of tumor transfection upon systemic administration in tumor-bearing mice. To be safely applicable in the clinic, it is crucial to investigate the colloidal stability of nanoparticles and to monitor the exact biodistribution of gene transfer in the whole body of the live subject. Our biophysical characterization shows that dendrimers, when complexed with DNA, are capable of forming spontaneously in solution a supramolecular assembly that possesses all the features required to diffuse in experimental tumors through the enhanced permeability and retention effect. We show that these nanoparticles are of sizes ranging from 33 to 286 nm depending on the DNA concentration, with a colloidal stable and well-organized fingerprint-like structure in which DNA molecules are condensed with an even periodicity of 2.8 nm. Whole-body nuclear imaging using small-animal nano-single-photon emission computed tomography/computer tomography scanner and the human Na/I symporter (NIS) as reporter gene shows unique and highly specific tumor targeting with no detection of gene transfer in any of the other tissues of tumor-bearing mice. Tumor-selective transgene expression was confirmed by quantitative reverse transcription-PCR at autopsy of scanned animals, whereas genomic PCR showed that the tumor sites are the predominant sites of nanoparticle accumulation. Considering that NIS imaging of transgene expression has been recently validated in humans, our data highlight the potential of these nanoparticles as a new formulation for cancer gene therapy.
Related JoVE Video
Amphiphilic poly(L-amino acids) - new materials for drug delivery.
J Control Release
Show Abstract
Hide Abstract
The formulation of drug compounds into medicines will increasingly rely on the use of specially tailored molecules, which fundamentally alter the drugs pharmacokinetics to enable its therapeutic activity. This is particularly true of the more challenging hydrophobic drugs or therapeutic biological molecules. The demand for such enabled medicines will translate into a demand for advanced highly functionalised drug delivery materials. Polymers have been used to formulate medicines for many decades and this is unlikely to change soon. Amphiphilic polymers based on amino acids are the subject of this review. These molecules, which present as either poly(L-amino acid) block copolymers or poly(L-amino acid) backbones with hydrophobic substituents, self assemble into micelles, vesicles, nanofibres and solid nanoparticles and such self assemblies, have drug delivery capabilities. The nature of the self-assembly depends on the chemistry of the constituent molecules, with the more hydrophilic molecules forming nanosized micellar aggregates including peptide nanofibres, molecules of intermediate hydrophobicity forming polymeric vesicles and the more hydrophobic variants forming amorphous polymeric nanoparticles of 100-1000 nm in diameter. The self-assemblies may be loaded with drugs or may present as micelle forming polymer-drug conjugates and the supramolecular aggregates have been employed as drug solubilisers, tumour targeting agents, gene delivery vectors and facilitators of intracellular drug uptake, with a more promising polymer-drug conjugate progressing to clinical testing.
Related JoVE Video
A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.
Mol. Pharm.
Show Abstract
Hide Abstract
The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood-brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine(5)-enkephalin, encapsulated within chitosan amphiphile nanoparticles. Via the oral route the nanoparticle-prodrug formulation increased the brain drug levels by 67% and significantly increased leucine(5)-enkephalins antinociceptive activity. The nanoparticles facilitate oral absorption and the prodrug prevents plasma degradation, enabling brain delivery. Via the intravenous route, the nanoparticle-prodrug increases the peptide brain levels by 50% and confers antinociceptive activity on leucine(5)-enkephalin. The nanoparticle-prodrug enables brain delivery by stabilizing the peptide in the plasma although the chitosan amphiphile particles are not transported across the blood-brain barrier per se, and are excreted in the urine.
Related JoVE Video
Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy.
J Biophotonics
Show Abstract
Hide Abstract
Advances in pharmaceutical nanotechnology have yielded ever increasingly sophisticated nanoparticles for medicine delivery. When administered via oral, intravenous, ocular and transcutaneous delivery routes, these nanoparticles can elicit enhanced drug performance. In spite of this, little is known about the mechanistic processes underlying interactions between nanoparticles and tissues, or how these correlate with improved pharmaceutical effects. These mechanisms must be fully understood before nanomedicines can be rationally engineered to optimise their performance. Methods to directly visualise these particulates within tissue samples have traditionally involved imaging modalities requiring covalent labelling of fluorescent or radioisotope contrast agents. We present CARS, second harmonic generation and two photon fluorescence microscopy combined as a multi-modal label-free method for pinpointing polymeric nanoparticles within the stomach, intestine, gall bladder and liver. We demonstrate for the first time that orally administered chitosan nanoparticles follow a recirculation pathway from the GI tract via enterocytes, to the liver hepatocytes and intercellular spaces and then to the gall bladder, before being re-released into the gut together with bile.
Related JoVE Video
Efficient synthesis and biological evaluation of proximicins A, B and C.
Bioorg. Med. Chem.
Show Abstract
Hide Abstract
A quick and efficient synthesis and the biological evaluation of promising antitumor-antibiotics proximicins A, B and C are reported. The characteristic repetitive unit of these molecules, the methyl 4-Boc-aminofuran-2-carboxylate 15, was prepared in three synthetic steps in good yield using an optimised copper-catalysed amidation method. The proximicins were evaluated for their antitumor activity using cellular methods. Proximicin B induced apoptosis in both Hodgkins lymphoma and T-cell leukemia cell lines and proximicin C exhibited significantly high cytotoxicity against glioblastoma and breast carcinoma cells. The proximicins were also screened against Escherichia coli, Enterococcus faecalis and several strains of methicillin-and multidrug-resistant Staphylococcus aureus. Proximicin B showed noteworthy activity against antibiotic-resistant Gram-positive cocci.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.