Monday, June 27, 2011

Scientists Develop Communicating Nanoparticles that Boost Targeted Drug Delivery to Tumors

Scientists have developed a two-stage communicating nanoparticle approach to tissue targeting and drug delivery that they claim can target 40 times higher doses of chemotherapeutics to tumors than traditional nanoparticles. Basing the new approach on communications systems found in nature such as insect swarming, immune-cell trafficking, and platelet self-assembly, the collaborative team led by Massachusetts Institute of Technology professor Sangeeta Bhatia, M.D., has devised a system that combines signaling nanoparticles or engineered proteins with receiving nanoparticles that carry the diagnostic or therapeutic agents.
Essentially, the signaling molecules home in on the tumor and activate the coagulation cascade, which results in recruitment of the clot-targeting receiving nanoparticles to the tumor site to deliver their cargo. Reporting in Nature Materials, the researchers claim their work provides the groundwork for a systems nanotechnology approach to targeting that could lead to more sensitive location, diagnosis, and treatment of tissue- or cell-specific diseases. Their paper is titled “Nanoparticles that communicate in vivo to amplify tumour targeting.”
Current approaches for targeting nanomaterials in vivo have focused on tuning the properties of individual nanoparticles (NPs) including their geometry, surface chemistry, ligand type, and ligand density, Dr. Bhatia and team notes. In contrast, the two-stage approach led by the MITresearchers and their collaborators uses two types of nanoparticles that work in concert.
They hypothesized that two signaling modules could selectively activate the coagulation cascade in tumors: NPs (gold nanorods, NRs) that target tumors and convert external electromagnetic energy into heat to locally disrupt tumor vessels, and engineered human proteins—more specifically tumor-targeted tissue factor, tTF—which autonomously survey host vessels for angiogenic tumor receptors and, in their presence, activate the extrinsic coagulation pathway. The receiving modules were constructed using a prototype imaging agent (magnetofluorescent iron oxide nanoworms, NWs) and a prototypical therapeutic agent comprising doxorubicin-loaded liposomes (LPs).
The first step was to test the capacity of the signaling modules to induce coagulation in tumors. Previous work had confirmed that PEG-coated gold NRs have a circulation half-life of over 17 hours in mice and can passively target tumors. The researchers intravenously administered PEG-NRs into tumor-bearing mice, and subsequently irradiated the treated tumors with near-infrared (NIR) light to increase focal tumor surface temperatures. After 24 hours the irradiated tumors in NR-treated mice demonstrated evidence that tumor blood vessel disruption had activated extravascular coagulation.
The researchers then moved on to investigate the potential for a biological signaling module to autonomously survey the host vasculature for angiogenic tumor receptors and, in their presence, engage the extrinsic coagulation cascade. This type of system would operate without the need for any external electromagnetic inputs (such as NIR energy) and could potentially amplify NP targeting to deep-seated and disseminated cancers, they note. For this the team used a truncated, tumor-targeted version of the human protein tissue factor (tTF-RGD), which harnesses an RGD peptide motif to induce coagulation on binding to angiogenic αvβ3 receptors. As occurred following PEG-NR administration, the tumors of mice injected with t-TF-RGD proteins also demonstrated vascular coagulation.
The next step was to construct receiving NPs that could efficiently target regions of coagulation and deliver therapeutics or imaging agents. To this end, a peptide substrate for the coagulation transglutaminase FXIII was tagged to magnetofluorescent iron oxide nanoworm imaging agents to act as an FXIII-NW imaging receiver.
Having verified the coagulation-targeting properties of the receiving FXIII-NW NPs in isolation, the researchers evaluated the two-stage signaling-receiving approach in combination. PEG-NRs were intravenously injected into mice bearing bilateral tumors. After NR clearance from circulation mixtures of active and inactive receiving NPs (FXIII-NWs and FXIIIControl-NWs) labelled with distinct NIR fluorochromes were co-injected intravenously, followed by NIR irradiation of just the right flank of the mouse.
Ninety-six hours later, imaging studies revealed pronounced homing of FXIII-NWs to the NR-heated tumors on the right flank, when compared both with the unirradiated tumor-bearing left flank, and with control, saline-injected mice. Histological examination showed that integrated NP generated intense regions of FXIII-NW fluorescence relative to controls, particularly in tumor boundaries where blood vessels were well perfused. Equivalent results were confirmed in different xengraft tumor models, which also demonstrated a several-fold amplification in the homing of targeted receiving NPs compared with untargeted controls.
In a separate set of experiments, the researchers evaluated the ability of autonomous communication between tTF-RGD signaling modules and FXIII-NW receiving modules to amplify tumor targeting. When co-injected alongside FXIII-NW receivers, the tTF-RGD signaling modules where shown to amplify the receiver targeting response several-fold compared with both noncommunicating controls and with NWs that are directly targeted by RGD-targeting ligands. Closer examination demonstrated that FXIII-NW receivers injected alongside tTF-RGD proteins produced a dendritic pattern of accumulation in tumors, corresponding to abundant intravascular localization immunohistochemically, the authors note. This amplified vascular targeting was found to be specific for tumors and was absent when the coagulation inhibitor heparin was administered alongside signaling and receiving modules.
To demonstrate proof of principal that the approach could improve tumor drug delivery and therapy, the researchers evaluated the efficacy of a therapeutic communicating nanosystem in which the receiver comprised doxorubicin-loaded LPs with tethered active FXIII. When these therapeutic receivers were used in place of the imaging receivers, the team was able to show that communication between NR signaling modules and FXIII-LP receivers amplified the accumulation of doxorubicin in NR-heated tumors by over 40-fold compared with LPs alone, and more than sixfold when compared with an optimized LP formulation that targeted endogenous vascular receptors (αvβ3 for high-affinity cyclic-RGD peptide-targeted LPs).
This amplification of drug delivery probably has at least two components, the authors suggest. Heat-dependent increases in passive accumulation due to improved extravasation in tumors, and specific biochemical recognition of the coagulation process by the peptide coating.
In a final set of studies the team evaluated the therapeutic efficacy of the communicating strategy using PEG-NRs as the signaling molecules and an intravenous dose of FXII-LPs in mice bearing a single human tumor. The PEG-NRs were injected into mice, and once cleared from the circulation, a single intravenous dose of FXIII-LP was given followed immediately by irradiation with NIR energy. The treatment resulted in prolonged inhibition of tumor growth that was significantly more effective than system components in isolation, without any detectable weight loss due to system toxicity.
“Given the diverse NP and synthetic biological 'building blocks' under development, coupled with the plethora of robust biological cascades that could be repurposed to enable communication between synthetic components, we believe that a wide array of nanosystems could be engineered to more sensitively locate, diagnose, and treat a diversity of focal human diseases,” the authors conclude. “We believe that this work motivates a paradigm of systems nanotechnology directed toward the construction of communicative diagnostic and therapeutic agents with sophisticated in vivo behaviors.”

Thursday, June 16, 2011

Feds, states split $25M in settlement

WASHINGTON (Legal Newsline) - The U.S. Justice Department announced on Friday that a Danish pharmaceutical manufacturer will pay $25 million to resolve its civil liability arising from the allegedly illegal promotion of its hemostasis management drug.
The Food and Drug Administration approved Novo Nordisk's hemostasis management drug NovoSeven to treat certain bleeding disorders in hemophiliacs. After FDA approval, a manufacturer may not market or promote a drug for uses not specified in its new drug application or for uses not approved by the FDA. Unapproved uses are known as "off-label" uses.
Novo Nordisk's U.S. subsidiary, which is located in Princeton, N.J., allegedly promoted NovoSeven to healthcare professionals for off-label uses, including as a coagulatory agent for trauma patients, general surgery, cardiac surgery, liver surgery, liver transplants and intra-cerebral hemorrhage.
False claims were submitted to government healthcare programs that were not reimbursable because of Novo Nordisk's unlawful promotion, it was alleged. The federal share of the civil settlement is $21,425,790.59. The state Medicaid share of the civil settlement is $3,574,209.41.
"Health care patients should be able to trust that their prescription drugs are safe, effective and prescribed only for FDA approved uses," Maine Attorney General William Schneider said. "These off-label promotions waste Maine taxpayer dollars and we will seek recovery from pharmaceutical companies for this kind of healthcare fraud."
The settlement resolves a a whistleblower lawsuit filed under the qui tam or whistleblower provisions of the False Claims Act that is pending in the District of Maryland. Under terms of the resolution, the whistleblowers are set to receive more than $3.5 million from the federal share of the civil recovery.
Novo Nordisk also agreed to enter into an expansive corporate integrity agreement with the Office of the Inspector General of the Department of Health and Human Services as part of the settlement. That agreement creates procedures and reviews meant to avoid and promptly detect similar conduct in the future.

Thursday, June 9, 2011

Jury Rules Against Baxter In Contaminated Chinese Heparin Case - "The Cheap Stuff"

An Illinois jury on Thursday awarded $625,000 to the estate of a Chicago-area man who was administered a blood-thinning drug that contained a contaminated ingredient medical-products company Baxter International Inc. (BAX) manufactured in China.
It was the first of hundreds of pending lawsuits against Baxter to go to trial.
The cases are related to a 2008 finding by the Food and Drug Administration, which discovered a link between contaminated heparin marketed by Baxter to Chinese suppliers of the active ingredient used in heparin. In the U.S., the contaminated heparin was linked to dozens of deaths and hundreds of allergic reactions.
Plaintiffs contended 63-year-old Steve Johansen received low doses of contaminated heparin during dialysis and a bolus dose during a subsequent hospitalization at Palos Community Hospital in late 2007.

The active pharmaceutical ingredient in the contaminated heparin received by Mr. Johansen and other Americans was obtained from Baxter/SPL's Chinese supplier, Changzhou SPL (a joint venture with SPL).  This crude heparin was referred to in the companies' own internal records as "the cheap stuff."  Baxter and SPL knew that the plant had never been inspected by the U.S. FDA (which the FDA later attributed to clerical error) or Chinese regulatory officials.  When the Chinese plant was finally inspected by the FDA after the heparin contamination crisis, multiple violations were found resulting in an import ban.  Additional evidence also brought to light during the trial established that Baxter and SPL failed to establish and comport with quality/purity specifications, including an impurity profile, and failed to trace and control their supply chain.  At trial, the Court granted partial directed verdict in favor of Mr. Johansen holding that the product sold by Baxter and SPL was defective as a matter of law.

According to the verdict, the award of compensation was for pain and suffering and was found against Baxter and the Chinese supplier, Scientific Protein Laboratories LLC.
Baxter spokeswoman Deborah Spak said the company is taking responsibility for legitimate cases of harm related to the contamination seriously, adding that Baxter will "vigorously defend claims that are not consistent with the definition established by public health authorities."
Baxter's therapies treat serious medical problems such as cancer, immune disorders and trauma. The company is coming off a challenging year due to economic weakness, costs pegged to the U.S. health-care overhaul and some product-quality and regulatory challenges.

Impact of Bleeding-related Complications and/or Blood Product Transfusions on Hospital Costs in Inpatient Surgical Patients

Inadequate surgical hemostasis may lead to transfusion and/or other bleeding-related complications. This study examines the incidence and costs of bleeding-related complications and/or blood product transfusions occurring as a consequence of surgery in various inpatient surgical cohorts. 
Methods: A retrospective analysis was conducted using Premier's Perspective hospital database.
Patients who had an inpatient procedure within a specialty of interest (cardiac, vascular, non-cardiac thoracic, solid organ, general, reproductive organ, knee/hip replacement, or spinal surgery) during 2006-2007 were identified. For each specialty, the rate of bleeding-related complications (including bleeding event, intervention to control for bleeding, and blood product transfusions) was examined, and hospital costs and length of stay (LOS) were compared between surgeries with and without bleeding-related complications.
Incremental costs and ratios of average total hospital costs for patients with bleeding-related complications vs. those without complications were estimated using ordinary least squares (OLS) regression, adjusting for demographics, hospital characteristics, and other baseline characteristics.
Models using generalized estimating equations (GEE) were also used to measure the impact of bleeding-related complications on costs while accounting for the effects related to the clustering of patients receiving care from the same hospitals. 

Results: A total of 103,829 cardiac, 216,199 vascular, 142,562 non-cardiac thoracic, 45,687 solid organ, 362,512 general, 384,132 reproductive organ, 246,815 knee/hip replacement, and 107,187 spinal surgeries were identified. Overall, the rate of bleeding-related complications was 29.9% and ranged from 7.5% to 47.4% for general reproductive organ and cardiac, respectively.

Overall, incremental LOS associated with bleeding-related complications or transfusions (unadjusted for covariates) was 6.0 days and ranged from 1.3 to 9.6 days for knee/hip replacement and non-cardiac thoracic, respectively. The incremental cost per hospitalization associated with bleeding-related complications and adjusted for covariates was highest for spinal surgery ($17,279) followed by vascular ($15,123), solid organ ($13,210), non-cardiac thoracic ($13,473), cardiac ($10,279), general ($4,354), knee/hip replacement ($3,005), and reproductive organ ($2,805). 

Conclusions: This study characterizes the increased hospital LOS and cost associated with bleeding-related complications and/or transfusions occurring as a consequence of surgery, and supports implementation of blood-conservation strategies.

Monday, June 6, 2011

In-vitro hemostasis test platform

An interesting new idea from Covidien could relieve the need for animal testing, while the pig and rats are used in most western countries, in China the animal of choice are dogs and rabbits. Regardless it is an interesting concept with other potential applications.

This paper appears in: Bioengineering Conference (NEBEC), 2011 IEEE 37th Annual Northeast 
Issue Date: 1-3 April 2011 
On page(s): 1 - 2 
Location: Troy, NY, USA 
ISSN: 2160-7001 
Print ISBN: 978-1-61284-827-3 
Digital Object Identifier: 10.1109/NEBC.2011.5778553  
Date of Current Version: 27 May 2011 

ABSTRACT


To avoid unnecessary preclinical testing of Covidien's hemostatic agent patch product, a test platform is needed to test the “time-to-hemostasis” of blood using the patch. The test platform needs to utilize in vitro testing, providing an alternative to in vivo testing. Understanding how “time-to-hemostasis” is affected by Covidien's various products will help surgeons prevent unnecessary bleeding when performing surgery, aid doctors healing large wounds from military events or other accidents, and will be useful in many other ways to prevent bleeding out that could fatally harm the patient. In order to stop the use of animal testing for this product, Covidien would like to have a bench-top in vitro testing device for their products. This device must be able to accurately simulate blood flow through a wound site, as well as simulate the hemostasis process of closing the wound through blood clotting. Important features of the finished device include accurate simulation of blood flow through a wounded tissue, accurately measure the time-to-hemostasis, and the ability to test multiple types of hemostat products efficiently. The device will provide Covidien with an in-house alternative to in vivo testing, saving time and expenditure when testing hemostats.

Thursday, June 2, 2011