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Home > Press > UNC-Chapel Hill researchers kill drug-resistant lung cancer with 50 times less chemo: Cancer drugs packaged in immune bubbles home in directly to tumors without getting sidetracked and destroyed; less chemo with better results Abstract: The cancer drug paclitaxel just got more effective. For the first time, researchers from the University of North Carolina at Chapel Hill have packaged it in containers derived from a patient's own immune system, protecting the drug from being destroyed by the body's own defenses and bringing the entire payload to the tumor. "That means we can use 50 times less of the drug and still get the same results," said Elena Batrakova, Ph.D., an associate professor in the UNC Eshelman School of Pharmacy. "That matters because we may eventually be able to treat patients with smaller and more accurate doses of powerful chemotherapy drugs resulting in more effective treatment with fewer and milder side effects." The work, led by Batrakova and her colleagues at the UNC Eshelman School of Pharmacy's Center for Nanotechnology in Drug Delivery, is based on exosomes, which are tiny spheres harvested from the white blood cells that protect the body against infection. The exosomes are made of the same material as cell membranes, and the patient's body doesn't recognize them as foreign, which has been one of the toughest issues to overcome in the past decade with using plastics-based nanoparticles as drug-delivery systems. "Exosomes are engineered by nature to be the perfect delivery vehicles," said Batrakova, who has also used this technique as a potential therapy for Parkinson's disease. "By using exosomes from white blood cells, we wrap the medicine in an invisibility cloak that hides it from the immune system. We don't know exactly how they do it, but the exosomes swarm the cancer cells, completely bypassing any drug resistance they may have and delivering their payload." Paclitaxel is a potent drug used in the United States as a first- and second-line treatment for breast, lung and pancreatic cancers. It can have serious and unpleasant side effects, such as hair loss, muscle and joint pain and diarrhea, and it can put patients at greater risk of serious infection. In their experiment, Batrakova's team extracted exosomes from mouse white blood cells and loaded them with paclitaxel. They then tested the treatment -- which they call exoPXT -- against multiple-drug-resistant cancer cells in petri dishes. The team saw that they needed 50 times less exoPXT to achieve the same cancer-killing effect as formulations of the drug currently being used, such as Taxol. The researchers next tested the therapy in mouse models of drug-resistant lung cancer. They loaded the exosomes with a dye in order to track their progress through the lungs and found that the exosomes were thorough in seeking out and marking cancer cells, making them a surprisingly effective diagnostic tool in addition to being a powerful therapeutic. "Accurately mapping the extent of tumors in the lungs is one of the biggest challenges in treating lung-cancer patients," said Batrakova. "Our results show how powerful exosomes can be as both a therapeutic and a diagnostic." ### Batrakova's study, which appears in Nanomedicine: Nanotechnology, Biology and Medicine, was supported by the National Institutes of Health and the Carolina Partnership, a strategic partnership between the UNC Eshelman School of Pharmacy and the University Cancer Research Fund through the Lineberger Comprehensive Cancer Center, as well as the Russian Federation Ministry of Education and Science. About University of North Carolina at Chapel Hill The University of North Carolina at Chapel Hill, the nation's first public university, is a global higher education leader known for innovative teaching, research and public service. A member of the prestigious Association of American Universities, Carolina regularly ranks as the best value for academic quality in U.S. public higher education. Now in its third century, the University offers 77 bachelor's, 113 master's, 68 doctorate and seven professional degree programs through 14 schools and the College of Arts and Sciences. Every day, faculty - including two Nobel laureates - staff and students shape their teaching, research and public service to meet North Carolina's most pressing needs in every region and all 100 counties. Carolina's more than 308,000 alumni live in all 50 states and 150 countries. More than 167,000 live in North Carolina. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Madden A.J.,University of North Carolina at Chapel Hill | Rawal S.,University of North Carolina at Chapel Hill | Sandison K.,University of North Carolina at Chapel Hill | Schell R.,University of North Carolina at Chapel Hill | And 8 more authors.
Journal of Nanoparticle Research | Year: 2014

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems. © 2014, Springer Science+Business Media Dordrecht.


Wadhwa S.,University of North Carolina at Chapel Hill | Mumper R.J.,University of North Carolina at Chapel Hill | Mumper R.J.,Center for Nanotechnology in Drug Delivery
Molecular Pharmaceutics | Year: 2010

D-Penicillamine is an aminothiol that is cytotoxic to cancer cells and generates dose dependent reactive oxygen species (ROS) via copper catalyzed oxidation. However, the delivery of d-pen to cancer cells remains a challenge due to its high hydrophilicity, highly reactive thiol group and impermeability to the cell membrane. To overcome this challenge, we investigated a novel poly-l-glutamic acid (PGA) conjugate of d-pen (PGA-d-pen) where d-pen was conjugated to PGA modified with 2-(2-pyridyldithio)-ethylamine (PDE) via disulfide bonds. Confocal microscopy and cell uptake studies showed that the fluorescently labeled PGA-d-pen was taken up by human leukemia cells (HL-60) in a time dependent manner. Treatment of HL-60, murine leukemia cells (P388) and human breast cancer cells (MDA-MB-468) with PGA-d-pen resulted in dose dependent cytotoxicity and elevation of intracellular ROS levels. PGA-d-pen induced apoptosis in HL-60 cells which was verified by Annexin V binding. The in vivo evaluation of the conjugate in the P388 murine leukemia model (intraperitoneal) resulted in significant enhancement in the survival of CD2F1 mice over vehicle control. © 2010 American Chemical Society.


Mullin L.,North Carolina State University | Ma P.,Center for Nanotechnology in Drug Delivery | Wadhwa S.,Center for Nanotechnology in Drug Delivery | Peng L.,Center for Nanotechnology in Drug Delivery | And 4 more authors.
Proceedings - IEEE Ultrasonics Symposium | Year: 2010

We propose that by utilizing acoustically-active delivery vehicles (AADVs),which combine the acoustic activity of an ultrasound contrast agent (UCA) withthe high payload and extravasation ability of nanoparticles, we can overcomelimitations of current chemotherapy delivery methodologies. AADV were formed byconjugating nanocapsules to the shell of biotinylated UCAs. Ultrasoundparameters were optimized with a 2.25 MHz focused transducer using a flowphantom to achieve both acoustic radiation force and microbubble destruction.R3230 cells cultured on a cover slip were exposed to the AADV and sonicated withthe focused transducer. Fluorescence microscopy verified binding ofnanocapsules to ultrasound contrast agents to form AADVs, and increased deliveryof nanocapsules to cells within the focus of the transducer (relative tonanocapsule delivery without ultrasound). An order-of-magnitude increase inparticles were delivered to cells exposed to ultrasound compared to unexposedcells. © 2010 IEEE.


Falcone J.A.,University of Washington | Falcone J.A.,Geriatrics Research Education and Clinical Center | Salameh T.S.,University of Washington | Salameh T.S.,Geriatrics Research Education and Clinical Center | And 8 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014

A variety of compounds will distribute into the brain when placed at the cribriform plate by intranasal (i.n.) administration. In this study, we investigated the ability of albumin, a protein that can act as a drug carrier but is excluded from brain by the bloodbrain barrier, to distribute into the brain after i.n. administration. We labeled bovine serum albumin with [125I] ([125I]Alb) and studied its uptake into 11 brain regions and its entry into the blood from 5 minutes to 6 hours after i.n. administration. [125I]Alb was present throughout the brain at 5 minutes. Several regions showed distinct peaks in uptake that ranged from 5 minutes (parietal cortex) to 60 minutes (midbrain). About 2-4% of the i.n. [125I]Alb entered the bloodstream. The highest levels occurred in the olfactory bulb and striatum. Distribution was dose-dependent, with less taken up by whole brain, cortex, and blood at the higher dose of albumin. Uptake was selectively increased into the olfactory bulb and cortex by the fluid-phase stimulator PMA (phorbol 12-myristate 13-acetate), but inhibitors to receptormediated transcytosis, caveolae, and phosphoinositide 3-kinase were without effect. Albumin altered the distribution of radioactive leptin given by i.n. administration, decreasing uptake into the blood and by the cerebellum and increasing uptake by the hypothalamus. We conclude that [125I]Alb administered i.n. reaches all parts of the brain through a dose-dependent mechanism that may involve fluid-phase transcytosis and, as illustrated by leptin, can affect the delivery of other substances to the brain after their i.n. administration. U.S. Government work not protected by U.S. copyright.


Yan B.,Ohio State University | Li B.,Ohio State University | Kunecke F.,Ohio State University | Gu Z.,University of North Carolina at Chapel Hill | And 2 more authors.
ACS Applied Materials and Interfaces | Year: 2015

Implantable devices for long-lasting controlled insulin microinjection are of great value to diabetic patients. To address this need, we develop a flexible electroactive pump based on a biocompatible polypyrrole composite film that comprises a polypyrrole matrix and a macromolecular dopant of polycaprolactone-block-polytetrahydrofuran-block-polycaprolactone. Using phosphate-buffered saline as the electrolyte, this film demonstrates much higher electroactivity and reproducibility than conventional Cl--doped polypyrrole, making it an excellent actuator for driving an implantable pump. At a driving current density of 1 mA/cm2, the pump demonstrates a consistent output capacity of 10.5 at 0.35 μL/s over 20 cycles. This work paves the way for the development of an implantable electroactive pump to improve the quality of life of diabetics. © 2015 American Chemical Society.


PubMed | Center for Nanotechnology in Drug Delivery and University of North Carolina at Chapel Hill
Type: | Journal: Journal of colloid and interface science | Year: 2016

Accessing the phase inversion temperature by microwave heating may enable the rapid synthesis of small lipid nanoparticles.Nanoparticle formulations consisted of surfactants Brij 78 and Vitamin E TPGS, and trilaurin, trimyristin, or miglyol 812 as nanoparticle lipid cores. Each formulation was placed in water and heated by microwave irradiation at temperatures ranging from 65C to 245C. We observed a phase inversion temperature (PIT) for these formulations based on a dramatic decrease in particle Z-average diameters. Subsequently, nanoparticles were manufactured above and below the PIT and studied for (a) stability toward dilution, (b) stability over time, (c) fabrication as a function of reaction time, and (d) transmittance of lipid nanoparticle dispersions.Lipid-based nanoparticles with distinct sizes down to 20-30nm and low polydispersity could be attained by a simple, one-pot microwave synthesis. This was carried out by accessing the phase inversion temperature using microwave heating. Nanoparticles could be synthesized in just one minute and select compositions demonstrated high stability. The notable stability of these particles may be explained by the combination of van der Waals interactions and steric repulsion. 20-30nm nanoparticles were found to be optically transparent.


PubMed | Center for Nanotechnology in Drug Delivery
Type: Journal Article | Journal: Journal of controlled release : official journal of the Controlled Release Society | Year: 2012

Lipid-based oil-filled nanoparticles (NPs) with a high concentration of surface-chelated nickel (Ni-NPs) were successfully prepared using a Brij 78-NTA-Ni conjugate synthesized with Brij 78 (Polyoxyethylene (20) stearyl ether) and nitrilotriacetic acid (NTA). The facile incorporation of the Brij 78-NTA-Ni conjugate into the NP formulation allowed up to 90% Ni incorporation, which was a significant improvement over the previously used standard agent DOGS-NTA-Ni which led to ~6% Ni incorporation. The Ni-NPs were targeted to the highly epidermal growth factor receptor (EGFR)-overexpressing epidermoid carcinoma cells A431. This was accomplished using a novel high affinity histidine6-tagged EGFR-binding Z domain (heptameric Z(EGFR) domain). In vitro cell uptake studies showed enhanced internalization (up to 90%) of the targeted Ni-NPs in A431 cells with only 10% internalization of the untargeted Ni-NPs. ICP-MS analysis used to quantify the amount of Ni in the cells were in close agreement with flow cytometry studies, which showed a dose dependent increase in the amount of Ni with the targeted Ni-NPs. Cell uptake competition studies showed that internalization of the targeted Ni-NPs within the cells was competed off with free heptameric Z(EGFR) domain at concentrations of 8.75ng/mL or higher. In vivo studies were carried out in nude mice bearing A431 tumors to determine the biodistribution and intracellular delivery. Near Infrared (NIR) optical imaging studies using Alexa750-labeled heptameric Z(EGFR) domain showed localization of 19% of the total detected fluorescence intensity in the tumor tissue, 28% in the liver and 42% in the kidneys 16h post i.v. injection. ICP-MS analysis showed almost a two-fold increase in the amount of intracellular Ni with the targeted Ni-NPs. These new Ni-NPs could be a very useful tool for targeting and drug delivery to a wide range of EGFR positive cancers.


PubMed | Center for Nanotechnology in Drug Delivery and University of North Carolina at Chapel Hill
Type: Journal Article | Journal: Journal of nanoparticle research : an interdisciplinary forum for nanoscale science and technology | Year: 2015

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC

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